In laboratory studies, scientists at the Johns Hopkins Kimmel Cancer Center have developed a way to personalise chemotherapy drug selection for cancer patients by using cell lines created from their own tumors.
If the technique is successful in further studies, it could replace current laboratory tests to optimise drug selection that have proven technically challenging, of limited use, and slow, the researchers say.
Oncologists typically choose anticancer drugs based on the affected organs’ location and/or the appearance and activity of cancer cells when viewed under a microscope. Some companies offer commercial tests on surgically removed tumours using a small number of anticancer drugs. But Anirban Maitra, MBBS, professor of pathology and oncology at the Johns Hopkins University School of Medicine, says the tissue samples used in such tests may have been injured by anaesthetic drugs or shipping to a lab, compromising test results.
By contrast, he says ‘our cell lines better and more accurately represent the tumours, and can be tested against any drug library in the world to see if the cancer is responsive.’
The Johns Hopkins scientists developed their test-worthy cell lines by injecting human pancreatic and ovarian tumour cells into mice genetically engineered to favour tumour growth. Once tumours grew to one centimetre in diameter in the mice, the scientists transferred the tumours to culture flasks for additional studies and tests with anticancer drugs.
In one experiment, they successfully pinpointed the two anticancer drugs from among more than 3,000 that were the most effective in killing cells in one of the pancreatic cancer cell lines
The new method was designed to overcome one of the central problems of growing human tumour cell lines in a laboratory dish — namely the tendency of non-cancerous cells in a tumour to overgrow cancerous ones, says James Eshleman, M.D., Ph.D., professor of pathology and oncology and associate director of the Molecular Diagnostics Laboratory at Johns Hopkins. As a consequence, it has not been possible to conventionally grow cell lines for some cancers. Still other cell lines, Eshleman says, don’t reflect the full spectrum of disease.
To solve the problem of overcrowding by non-cancerous cells, Maitra and Eshleman bred genetically engineered mice that replace the non-cancerous cells with mouse cells that can be destroyed by chemicals, leaving pure human tumour cells for study.
‘Our technique allows us to produce cell lines where they don’t now exist, where more lines are needed, or where there is a particularly rare or biologically distinctive patient we want to study,’ says Eshleman.
John Hopkin’s Hospital
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Diagnosed in toddlers, X-linked hypophosphatemia (XLH) is the most common form of heritable rickets, in which soft bones bend and deform, and tooth abscesses develop because infections penetrate soft teeth that are not properly calcified. Researchers at McGill University and the Federal University of Sao Paulo have identified that osteopontin, a major bone and tooth substrate protein, plays a role in XLH. Their discovery may pave the way to effectively treating this rare disease.
The findings were made by the laboratories of Marc McKee, a professor in the Faculty of Dentistry and the Department of Anatomy and Cell Biology at McGill University, and of Nilana M.T. Barros, a professor at the Federal University of Sao Paulo. The team built upon previous research that had shown that mutations in the single gene PHEX are responsible for causing XLH.
‘XLH is caused in part by renal phosphate wasting, which is the urinary loss from the body of phosphate, an important building block of bones and teeth, along with calcium.’ says Prof. McKee. ‘In pursuing other factors that might contribute to XLH, we used a variety of research methods to show that PHEX enzymatic activity leads to an essentially complete degradation of osteopontin in bones.’
This loss of osteopontin, a known potent inhibitor of mineralisation (or calcification) in the skeleton and dentition, normally allows bones and teeth to mineralise and thus harden to meet the biomechanical demands placed on them. In XLH patients lacking functional PHEX enzyme, osteopontin and some of its smaller potent inhibitory peptides are retained and accumulate within the bone. This prevents their hardening and leads to soft deformed bones such as bowed legs (or knock-knees) seen in toddlers.
While not life-threatening, this decreased mineralisation of the skeleton (osteomalacia), along with the soft teeth, soon leads to a waddling gait, short stature, bone and muscle pain, weakness and spontaneous tooth abscesses.
The fact that these symptoms are only partially improved by the standard treatment with phosphate – which improves circulating phosphate levels – prompted the researchers to look for local factors within the bone that might be blocking mineralisation in these patients.
‘With this new identification of osteopontin as a substrate protein for PHEX,’ says Professor Barros, ‘we can begin to develop an enzyme-replacement therapy to treat XLH patients who have non-functional PHEX, much as has been done using a different enzyme to treat another rare bone disease called hypophosphatasia.’
McGill University
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New findings by Columbia researchers suggest that along with amyloid deposits, white matter hyperintensities (WMHs) may be a second necessary factor for the development of Alzheimer’s disease.
Most current approaches to Alzheimer’s disease focus on the accumulation of amyloid plaque in the brain. The researchers at the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, led by Adam M. Brickman, PhD, assistant professor of neuropsychology, examined the additional contribution of small-vessel cerebrovascular disease, which they visualised as white matter hyperintensities (WMHs).
The study included 20 subjects with clinically defined Alzheimer’s disease, 59 subjects with mild cognitive impairment, and 21 normal control subjects. Using data from the Alzheimer’s Disease Neuro-imaging Initiative public database, the researchers found that amyloid and WHMs were equally associated with an Alzheimer’s diagnosis. Amyloid and WMHs were also equally predictive of which subjects with mild-cognitive impairment would go on to develop Alzheimer’s. Among those with significant amyloid, WMHs were more prevalent in those with Alzheimer’s than in normal control subjects.
Because the risk factors for WMHs—which are mainly vascular—can be controlled, the findings suggest potential ways to prevent the development of Alzheimer’s in those with amyloid deposits.
Columbia University Medical Center
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Researchers at the University of Wisconsin-Madison have found a new way to accelerate a workhorse instrument that identifies proteins. The high-speed technique could help diagnose cancer sooner and point to new drugs for treating a wide range of conditions.
Proteins are essential building blocks of biology, used in muscle, brain, blood and hormones. If the genes are the blueprints, the proteins patterned on them are the hammers and tongs of life.
Proteins are not only numerous — humans have more than 100,000 varieties — but each one has a complex structure that determines its exact function in the biological realm. Just as tissue from cats and kangaroos can be distinguished by studying the individual ‘letters’ of their genetic codes, protein A can be distinguished from protein B by looking at the amino-acid sub-units that compose all proteins.
The fastest way to count and identify proteins is to use a mass spectrometer, a precise instrument that measures chemical compounds by mass. ‘Mass spec is an essential part of modern biology, and most people use it to look at variations in proteins,’ says Joshua Coon, a professor of chemistry and biomolecular chemistry.
Because mass spectrometers are expensive, and proteins are both numerous and ubiquitous, chemists have recently learned to double up their samples so they can, for example, compare normal tissue to diseased tissue in a single run.
Knowing how the proteins change when good tissue goes bad suggests what has gone wrong.
Now, Coon has doubled-down on the doubling-up process with a technique that has the potential to run as many as 20 samples at once. The new process has already gone to work, says Alexander Hebert, a graduate student who was first author on the new publication.
‘Working with John Denu at the Wisconsin Institute for Discovery, we are looking at mice that lived with or without caloric restriction,’ says Hebert. Caloric restriction is known to increase lifespan in many animals, and scientists are eager to unravel the biochemical pathways that explain this life extension. ‘Some of these mice have lost a certain gene related to metabolism, so we are comparing four types of tissue all at once. We can look at the brain, liver or heart, and ask, how does the abundance of proteins vary?’
Already, Coon and Hebert have performed six simultaneous analyses using the new technique; but it could actually do batches of 20, Coon says.
Key to the original doubling-up process was inserting a ‘tag’ into the amino acids that gives the proteins a slightly different mass. The tags are isotopes — chemically identical atoms that have different masses.
To prepare two samples, one would receive an amino acid containing common isotopes, and the other special, heavier isotopes. The result — proteins that are chemically identical but have different masses — can easily be identified in a mass spectrometer.
The new journal report by Coon and Hebert describes a way to use amino acids built from a broader range of isotopes that would be expected to have identical mass, but do not because some of their mass has been converted to energy to hold the atomic nuclei together. Without this energy, the positively charged proteins would repel each other and the atomic nucleus would be destroyed. The tiny loss of mass due to this conversion to binding energy can be detected in the new, ultra-precise mass spectrometers that are now installed in several labs on campus.
The mass difference in the new technique is more than 1,000 times below the mass differences in the existing doubled-up technique, but it is enough to count and identify proteins from six — and, theoretically, 20 — samples at once. The researchers applied for a patent last fall and assigned the rights to the Wisconsin Alumni Research Foundation.
University of Wisconsin-Madison
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Psychogenic diseases, formerly known as ‘hysterical’ illnesses, can have many severe symptoms such as painful cramps or paralysis but without any physical explanation. However, new research from the University of Cambridge and UCL (University College London) suggests that individuals with psychogenic disease, that is to say physical illness that stems from emotional or mental stresses, do have brains that function differently.
Psychogenic diseases may look very similar to illnesses caused by damage to nerves, the brain or the muscles, or similar to genetic diseases of the nervous system. However, unlike organic diseases, psychogenic diseases do not have any apparent physical cause, making them difficult to diagnose and even more difficult to treat.
‘The processes leading to these disorders are poorly understood, complex and highly variable. As a result, treatments are also complex, often lengthy and in many cases there is poor recovery. In order to improve treatment of these disorders, it is important to first understand the underlying mechanism,’ said Dr James Rowe from the University of Cambridge.
The study looked at people with either psychogenic or organic dystonia, as well as healthy people with no dystonia. Both types of dystonia caused painful and disabling muscle contractions affecting the leg. The organic patient group had a gene mutation (the DYT1 gene) that caused their dystonia. The psychogenic patients had the symptoms of dystonia but did not have any physical explanation for the disease, even after extensive investigations.
The scientists performed PET brain scans on the volunteers at UCL, to measure the blood flow and brain activity of both of the groups, and healthy volunteers. The participants were scanned with three different foot positions: resting, moving their foot, and holding their leg in a dystonic position. The electrical activity of the leg muscles was measured at the same time to determine which muscles were engaged during the scans.
The researchers found that the brain function of individuals with the psychogenic illness was not normal. The changes were, however, very different from the brains of individuals with the organic (genetic) disease.
Dr Anette Schrag, from UCL, said: ‘Finding abnormalities of brain function that are very different from those in the organic form of dystonia opens up a way for researchers to learn how psychological factors can, by changing brain function, lead to physical problems.’
Dr Rowe added: ‘What struck me was just how very different the abnormal brain function was in patients with the genetic and the psychogenic dystonia. Even more striking was that the differences were there all the time, whether the patients were resting or trying to move.’
Additionally, the researchers found that one part of the brain previously thought to indicate psychogenic disease is unreliable: abnormal activity of the prefrontal cortex was thought to be the hallmark of psychogenic diseases. In this study, the scientists showed that this abnormality is not unique to psychogenic disease, since activity was also present in the patients with the genetic cause of dystonia when they tried to move their foot.
Dr Arpan Mehta, from the University of Cambridge, said: ‘It is interesting that, despite the differences, both types of patient had one thing in common – a problem at the front of the brain. This area controls attention to our movements and although the abnormality is not unique to psychogenic dystonia, it is part of the problem.’
This type of illness is very common. Dr Schrag said: ‘One in six patients that see a neurologist has a psychogenic illness. They are as ill as someone with organic disease, but with a different cause and different treatment needs. Understanding these disorders, diagnosing them early and finding the right treatment are all clearly very important. We are hopeful that these results might help doctors and patients understand the mechanism leading to this disorder, and guide better treatments.’
University of Cambridge
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Researchers at Karolinska Institutet in Sweden have identified a new so-called pseudogene that regulates the tumour-suppressing PTEN gene. They hope that this pseudogene will be able to control PTEN to reverse the tumour process, make the cancer tumour more sensitive to chemotherapy and to prevent the development of resistance.
The development of tumours coincides with the activation of several cancer genes as well as the inactivation of other tumour-suppressing genes owing to damage to the DNA and to the fact that the cancer cells manage to switch off the transcription of tumour-suppressor genes. To identify what might be regulating this silencing, the researchers studied PTEN, one of the most commonly inactivated tumour-suppressor genes. It has long been believed that the switching-off process is irreversible, but the team has now shown that silenced PTEN genes in tumour cells can be ‘rescued’ and re-activated by a ‘pseudogene’, a type of gene that, unlike normal genes, does not encode an entire protein.
‘We identified a new non-protein encoding pseudogene, which determines whether the expression of PTEN is to be switched on or off,’ says research team member Per Johnsson, doctoral student at Karolinska Institutet’s Department of Oncology-Pathology. ‘What makes this case spectacular is that the gene only produces RNA, the protein’s template. It is this RNA that, through a sequence of mechanisms, regulates PTEN. Pseudogenes have been known about for many years, but it was thought that they were only junk material.’
No less than 98 per cent of human DNA consists of non-protein encoding genes (i.e. pseudogenes), and by studying these formerly neglected genes the researchers have begun to understand that they are very important and can have an effect without encoding proteins. Using model systems, the team has shown that the new pseudogene can control the expression of PTEN and make tumours more responsive to conventional chemotherapy.
‘This means that we might one day be able to re-programme cancer cells to proliferate less, become more normal, and that resistance to chemotherapy can hopefully be avoided,’ says Per Johnsson. ‘We also believe that our findings can be very important for the future development of cancer drugs. What we’re seeing here is just the tip of the iceberg. The human genome conceals no less than 15,000 or so pseudogenes, and it’s not unreasonable to think that many of them are relevant to diseases such as cancer.’
Karolinska Institutet
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Foetal alcohol syndrome is the leading preventable cause of developmental disorders in developed countries. And foetal alcohol spectrum disorder (FASD), a range of alcohol-related birth defects that includes foetal alcohol syndrome, is thought to affect as many as 1 in 100 children born in the United States.
Any amount of alcohol consumed by the mother during pregnancy poses a risk of FASD, a condition that can include the distinct pattern of facial features and growth retardation associated with foetal alcohol syndrome as well as intellectual disabilities, speech and language delays, and poor social skills. But drinking can have radically different outcomes for different women and their babies. While twin studies have suggested a genetic component to susceptibility to FASD, researchers have had little success identifying who is at greatest risk or what genes are at play.
Research from Harvard Medical School and Veterans Affairs Boston Healthcare System sheds new light on this question, identifying for the first time a signalling pathway that might determine genetic susceptibility for the development of FASD.
‘Our work points to candidate genes for FASD susceptibility and identifies a path for the rational development of drugs that prevent ethanol neurotoxicity,’ said Michael Charness, chief of staff at VA Boston Healthcare System and HMS professor of neurology. ‘And importantly, identifying those mothers whose foetuses are most at risk could help providers better target intensive efforts at reducing drinking during pregnancy.’
The discovery also solves a riddle that had intrigued Charness and other researchers for nearly two decades. In 1996, Charness and colleagues discovered that alcohol disrupted the work of a human protein critical to foetal neural development—a major clue to the biological processes of FASD. The protein, L1, projects through the surface of a cell to help it adhere to its neighbours. When Charness and his team introduced the protein to a culture of mouse fibroblasts cells, L1 increased cell adhesion. Tellingly, the effect was erased in the presence of ethanol (beverage alcohol).
Charness and his team went on to develop multiple cell lines from that first culture, and that’s where they encountered the riddle: In some of those lines, alcohol disrupted L1’s adhesive effect, while in others it did not.
‘How could it be possible that a cell that expresses L1 is completely sensitive to alcohol, and others that express it are completely insensitive?’ asked Charness, who is also faculty associate dean for veterans hospital programs at HMS and assistant dean at Boston University School of Medicine.
Clearly, something else was affecting the protein’s sensitivity to alcohol — but what? Studies of twins provided one clue: Identical twins are more likely than fraternal twins to have the same diagnosis, positive or negative, for FASD. ‘That concordance suggests that there are modifying genes, susceptibility genes, that predispose to this condition,’ Charness said.
In the current study, Charness’ team and collaborators at the University of North Carolina School of Medicine in Chapel Hill conducted cell culture experiments to identify specific molecular events that contribute to the alcohol sensitivity of L1 adhesion molecules. They focused on what was happening to the L1 molecule inside a cell that could affect an event outside the cell such as disruption by alcohol.
‘We found that phosphorylation events that begin inside the cell can render the external portion of the L1 adhesion molecule more vulnerable to inhibition by alcohol,’ said Xiaowei Dou, HMS instructor in neurology in the Charness Lab and first author on the new study. ‘Phosphorylation was controlled by the enzyme ERK2, and occurred at a specific location on the internal portion of the L1molecule.’
Phosphorylation plays a significant role in a wide range of cellular processes. By adding a phosphate group to a protein or other molecule, phosphorylation turns many protein enzymes on and off, and thereby alters their function and activity.
The researchers also found that variations in ERK2 activity correlated with differences in L1 sensitivity to alcohol that they observed across cell lines and among different strains of mice. ‘Dou showed that he could take these cells that had been insensitive to alcohol for 13-14 years, and make them sensitive by ramping up the activity of this kinase’ Charness said.
These variations suggest that genes for ERK2 and the signalling molecules that regulate ERK2 activity might influence genetic susceptibility to FASD. Moreover, their identification of a specific locus that regulates the alcohol sensitivity of L1 might facilitate the rational design of drugs that block alcohol neurotoxicity.
‘The only thing this modification blocked was alcohol’s ability to inhibit L1,’ Charness said. ‘If you’re looking for a drug, ideally you’re looking for it to block the effects of the toxin without interfering with the target molecule of the toxin.’
The findings will also help guide an international consortium in its search for genes linked to families with fetal alcohol spectrum disorders.
Harvard Medical School
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Unusually high calcium levels in the blood can almost always be traced to primary hyperparathyroidism, an under-treated, underreported condition that affects mainly women and the elderly, according to a new study by UCLA researchers.
The condition, which results from overactive parathyroid glands and includes symptoms of bone loss, depression and fatigue that may go undetected for years, is most often seen in African American women over the age of 50, the researchers discovered.
The study is one of the first to examine a large, racially and ethnically diverse population — in this case, one that was 65 percent non-white. Previous studies had focused on smaller, primarily Caucasian populations.
The four parathyroid glands, which are located in the neck, next to the thyroid, regulate the body’s calcium levels. When one is dysfunctional, it can cause major imbalances — for example, by releasing calcium from the bones and into the bloodstream. Over time, calcium loss from bones often leads to osteoporosis and fractures, and excessive calcium levels in the blood can cause kidney stones and worsening kidney function.
The UCLA researchers determined that hyperparathyroidism is the leading cause of high blood-calcium levels and is responsible for nearly 90 percent of all cases.
‘The findings suggest that hyperparathyroidism is the predominant cause of high calcium levels, so if patients find they have high calcium, they should also have their parathyroid hormone level checked,’ said the study’s lead author, Dr. Michael W. Yeh, an associate professor of surgery and endocrinology at the David Geffen School of Medicine at UCLA.
Hyperparathyroidism, which affects approximately 1 percent of the population, can be detected by measuring parathyroid hormone levels to determine if they are elevated or abnormal.
UCLA
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A JDRF-funded study out of Switzerland has shown that a single gene called SIRT1 may be involved in the development of type 1 diabetes (T1D) and other autoimmune diseases. The study represents the first demonstration of a mono-genetic defect leading to the onset of T1D.
The research began when Marc Donath, M.D., endocrinologist and researcher at the University Hospital Basel in Switzerland, discovered an interesting pattern of autoimmune disease within the family of one of his patients, a 26-year-old male who had recently been diagnosed with T1D. The patient showed an uncommonly strong family history of T1D; his sister, father, and paternal cousin had also been diagnosed earlier in their lives. Additionally, another family member had developed ulcerative colitis, also an autoimmune disease.
‘This pattern of inheritance was indicative of dominant genetic mutation, and we therefore decided to attempt to identify it,’ Dr. Donath said.
Four years of analysis using three different genotyping and sequencing techniques pointed to a mutation on the SIRT1 gene as the common indicator of autoimmune disease within the family. The SIRT1 gene plays a role in regulating metabolism and protecting against age-related disease. To gain more understanding of how this genetic change in SIRT1 leads to T1D, Dr. Donath and his team performed additional studies with animal models of T1D. When the mutant SIRT1 gene found in the families was expressed in beta cells, those beta cells generated more mediators that were destructive to them. Furthermore, knocking out the normal SIRT1 gene in mice resulted in their becoming more susceptible to diabetes with greatly increased islet destruction. Dr. Donath speculates that the beta cell impairment and death due to the SIRT1 mutation subsequently activates the immune system toward T1D.
‘The identification of a gene leading to type 1 diabetes could allow us to understand the mechanism responsible for the disease and may open up new treatment options,’ Dr. Donath explained.
Patricia Kilian, Ph.D., director of the Beta Cell Regeneration Program at JDRF, concurred, and said that the development is exciting for many reasons: ‘While the change in the genetic makeup within this family with type 1 diabetes is rare, the discovery of the role of the SIRT1 pathway in affecting beta cells could help scientists find ways to enhance beta cell survival and function in more common forms of the disease. This study also reinforces increasing evidence that abnormal beta cell function has a role in the development of type 1 diabetes, and that blocking or reversing early stages of beta cell dysfunction may help prevent or significantly delay the disease’s onset. Drug companies are already in the process of developing SIRT1 activators, which could eventually speed our ability to translate these new research findings into meaningful therapies for patients.’
JDRF
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Researchers at Columbia University Medical Center (CUMC), with collaborators at the Albert Einstein College of Medicine of Yeshiva University, have discovered how the most common genetic mutations in familial Parkinson’s disease damage brain cells. The mutations block an intracellular system that normally prevents a protein called alpha-synuclein from reaching toxic levels in dopamine-producing neurons. The findings suggest that interventions aimed at enhancing this digestive system, or preventing its disruption, may prove valuable in the prevention or treatment of Parkinson’s.
Parkinson’s disease is characterised by the formation of Lewy bodies (which are largely composed of alpha-synuclein) in dopamine neurons. In 1997, scientists discovered that a mutation in alpha-synuclein can lead to Lewy body formation. ‘But alpha-synuclein mutations occur in only a tiny percentage of Parkinson’s patients,’ said co-lead author David L. Sulzer, PhD, professor of neurology, pharmacology, and psychiatry at CUMC. ‘This meant that there must be something else that interfered with alpha-synuclein in people with Parkinson’s.’
Dr. Sulzer and his colleagues suspected that a gene called leucine-rich repeat kinase-2 (LRRK2) might be involved. LRRK2 mutations are the most common mutations to have been linked to Parkinson’s. The current study aimed to determine how these mutations might lead to the accumulation of alpha-synuclein.
‘We found that abnormal forms of LRRK2 protein disrupt a critical protein-degradation process in cells called chaperone-mediated autophagy,’ said Dr. Sulzer. ‘One of the proteins affected by this disruption is alpha-synuclein. As this protein starts to accumulate, it becomes toxic to neurons.’ Delving deeper, the researchers found that LRRK2 mutations interfere with LAMP-2A, a lysosome membrane receptor that plays a key role in lysosome function.
‘Now that we know this step that may be causing the disease in many patients, we can begin to develop drug treatments or genetic treatments that can enhance the digestion of these disease-triggering proteins, alpha-synuclein and LRRK2, or that remove alpha-synuclein,’ said Dr. Sulzer.
While LRRK2 mutations are the most common genetic cause of Parkinson’s, it is too early to tell whether these findings, and therapies that might stem from them, would apply to patients with non-familial Parkinson’s, the more common form of the disease. ‘Right now, all we can say is that it looks as though we’ve found a fundamental pathway that causes the buildup of alpha-synuclein in people with LRRK2 mutations and links these mutations to a common cause of the disease. We suspect that this pathway may be involved in many other Parkinson’s patients,’ said Dr. Sulzer.
The study involved mouse neurons in tissue culture from four different animal models, neurons from the brains of patients with Parkinson’s with LRRK2 mutations, and neurons derived from the skin cells of Parkinson’s patients via induced pluripotent stem (iPS) cell technology. All the lines of research confirmed the researchers’ discovery.
Columbia University Medical Center
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Scientists create method to personalise chemotherapy drug selection
, /in E-News /by 3wmediaIn laboratory studies, scientists at the Johns Hopkins Kimmel Cancer Center have developed a way to personalise chemotherapy drug selection for cancer patients by using cell lines created from their own tumors.
If the technique is successful in further studies, it could replace current laboratory tests to optimise drug selection that have proven technically challenging, of limited use, and slow, the researchers say.
Oncologists typically choose anticancer drugs based on the affected organs’ location and/or the appearance and activity of cancer cells when viewed under a microscope. Some companies offer commercial tests on surgically removed tumours using a small number of anticancer drugs. But Anirban Maitra, MBBS, professor of pathology and oncology at the Johns Hopkins University School of Medicine, says the tissue samples used in such tests may have been injured by anaesthetic drugs or shipping to a lab, compromising test results.
By contrast, he says ‘our cell lines better and more accurately represent the tumours, and can be tested against any drug library in the world to see if the cancer is responsive.’
The Johns Hopkins scientists developed their test-worthy cell lines by injecting human pancreatic and ovarian tumour cells into mice genetically engineered to favour tumour growth. Once tumours grew to one centimetre in diameter in the mice, the scientists transferred the tumours to culture flasks for additional studies and tests with anticancer drugs.
In one experiment, they successfully pinpointed the two anticancer drugs from among more than 3,000 that were the most effective in killing cells in one of the pancreatic cancer cell lines
The new method was designed to overcome one of the central problems of growing human tumour cell lines in a laboratory dish — namely the tendency of non-cancerous cells in a tumour to overgrow cancerous ones, says James Eshleman, M.D., Ph.D., professor of pathology and oncology and associate director of the Molecular Diagnostics Laboratory at Johns Hopkins. As a consequence, it has not been possible to conventionally grow cell lines for some cancers. Still other cell lines, Eshleman says, don’t reflect the full spectrum of disease.
To solve the problem of overcrowding by non-cancerous cells, Maitra and Eshleman bred genetically engineered mice that replace the non-cancerous cells with mouse cells that can be destroyed by chemicals, leaving pure human tumour cells for study.
‘Our technique allows us to produce cell lines where they don’t now exist, where more lines are needed, or where there is a particularly rare or biologically distinctive patient we want to study,’ says Eshleman. John Hopkin’s Hospital
Elusive substrate protein identified in the most common form of heritable rickets
, /in E-News /by 3wmediaDiagnosed in toddlers, X-linked hypophosphatemia (XLH) is the most common form of heritable rickets, in which soft bones bend and deform, and tooth abscesses develop because infections penetrate soft teeth that are not properly calcified. Researchers at McGill University and the Federal University of Sao Paulo have identified that osteopontin, a major bone and tooth substrate protein, plays a role in XLH. Their discovery may pave the way to effectively treating this rare disease.
The findings were made by the laboratories of Marc McKee, a professor in the Faculty of Dentistry and the Department of Anatomy and Cell Biology at McGill University, and of Nilana M.T. Barros, a professor at the Federal University of Sao Paulo. The team built upon previous research that had shown that mutations in the single gene PHEX are responsible for causing XLH.
‘XLH is caused in part by renal phosphate wasting, which is the urinary loss from the body of phosphate, an important building block of bones and teeth, along with calcium.’ says Prof. McKee. ‘In pursuing other factors that might contribute to XLH, we used a variety of research methods to show that PHEX enzymatic activity leads to an essentially complete degradation of osteopontin in bones.’
This loss of osteopontin, a known potent inhibitor of mineralisation (or calcification) in the skeleton and dentition, normally allows bones and teeth to mineralise and thus harden to meet the biomechanical demands placed on them. In XLH patients lacking functional PHEX enzyme, osteopontin and some of its smaller potent inhibitory peptides are retained and accumulate within the bone. This prevents their hardening and leads to soft deformed bones such as bowed legs (or knock-knees) seen in toddlers.
While not life-threatening, this decreased mineralisation of the skeleton (osteomalacia), along with the soft teeth, soon leads to a waddling gait, short stature, bone and muscle pain, weakness and spontaneous tooth abscesses.
The fact that these symptoms are only partially improved by the standard treatment with phosphate – which improves circulating phosphate levels – prompted the researchers to look for local factors within the bone that might be blocking mineralisation in these patients.
‘With this new identification of osteopontin as a substrate protein for PHEX,’ says Professor Barros, ‘we can begin to develop an enzyme-replacement therapy to treat XLH patients who have non-functional PHEX, much as has been done using a different enzyme to treat another rare bone disease called hypophosphatasia.’ McGill University
It’s not just amyloid: White matter hyperintensities and Alzheimer’s Disease
, /in E-News /by 3wmediaNew findings by Columbia researchers suggest that along with amyloid deposits, white matter hyperintensities (WMHs) may be a second necessary factor for the development of Alzheimer’s disease.
Most current approaches to Alzheimer’s disease focus on the accumulation of amyloid plaque in the brain. The researchers at the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, led by Adam M. Brickman, PhD, assistant professor of neuropsychology, examined the additional contribution of small-vessel cerebrovascular disease, which they visualised as white matter hyperintensities (WMHs).
The study included 20 subjects with clinically defined Alzheimer’s disease, 59 subjects with mild cognitive impairment, and 21 normal control subjects. Using data from the Alzheimer’s Disease Neuro-imaging Initiative public database, the researchers found that amyloid and WHMs were equally associated with an Alzheimer’s diagnosis. Amyloid and WMHs were also equally predictive of which subjects with mild-cognitive impairment would go on to develop Alzheimer’s. Among those with significant amyloid, WMHs were more prevalent in those with Alzheimer’s than in normal control subjects.
Because the risk factors for WMHs—which are mainly vascular—can be controlled, the findings suggest potential ways to prevent the development of Alzheimer’s in those with amyloid deposits. Columbia University Medical Center
Analytical trick may accelerate cancer diagnosis
, /in E-News /by 3wmediaResearchers at the University of Wisconsin-Madison have found a new way to accelerate a workhorse instrument that identifies proteins. The high-speed technique could help diagnose cancer sooner and point to new drugs for treating a wide range of conditions.
Proteins are essential building blocks of biology, used in muscle, brain, blood and hormones. If the genes are the blueprints, the proteins patterned on them are the hammers and tongs of life.
Proteins are not only numerous — humans have more than 100,000 varieties — but each one has a complex structure that determines its exact function in the biological realm. Just as tissue from cats and kangaroos can be distinguished by studying the individual ‘letters’ of their genetic codes, protein A can be distinguished from protein B by looking at the amino-acid sub-units that compose all proteins.
The fastest way to count and identify proteins is to use a mass spectrometer, a precise instrument that measures chemical compounds by mass. ‘Mass spec is an essential part of modern biology, and most people use it to look at variations in proteins,’ says Joshua Coon, a professor of chemistry and biomolecular chemistry.
Because mass spectrometers are expensive, and proteins are both numerous and ubiquitous, chemists have recently learned to double up their samples so they can, for example, compare normal tissue to diseased tissue in a single run.
Knowing how the proteins change when good tissue goes bad suggests what has gone wrong.
Now, Coon has doubled-down on the doubling-up process with a technique that has the potential to run as many as 20 samples at once. The new process has already gone to work, says Alexander Hebert, a graduate student who was first author on the new publication.
‘Working with John Denu at the Wisconsin Institute for Discovery, we are looking at mice that lived with or without caloric restriction,’ says Hebert. Caloric restriction is known to increase lifespan in many animals, and scientists are eager to unravel the biochemical pathways that explain this life extension. ‘Some of these mice have lost a certain gene related to metabolism, so we are comparing four types of tissue all at once. We can look at the brain, liver or heart, and ask, how does the abundance of proteins vary?’
Already, Coon and Hebert have performed six simultaneous analyses using the new technique; but it could actually do batches of 20, Coon says.
Key to the original doubling-up process was inserting a ‘tag’ into the amino acids that gives the proteins a slightly different mass. The tags are isotopes — chemically identical atoms that have different masses.
To prepare two samples, one would receive an amino acid containing common isotopes, and the other special, heavier isotopes. The result — proteins that are chemically identical but have different masses — can easily be identified in a mass spectrometer.
The new journal report by Coon and Hebert describes a way to use amino acids built from a broader range of isotopes that would be expected to have identical mass, but do not because some of their mass has been converted to energy to hold the atomic nuclei together. Without this energy, the positively charged proteins would repel each other and the atomic nucleus would be destroyed. The tiny loss of mass due to this conversion to binding energy can be detected in the new, ultra-precise mass spectrometers that are now installed in several labs on campus.
The mass difference in the new technique is more than 1,000 times below the mass differences in the existing doubled-up technique, but it is enough to count and identify proteins from six — and, theoretically, 20 — samples at once. The researchers applied for a patent last fall and assigned the rights to the Wisconsin Alumni Research Foundation. University of Wisconsin-Madison
Study reveals how people with a severe unexplained psychological illness have abnormal activity in the brain.
, /in E-News /by 3wmediaPsychogenic diseases, formerly known as ‘hysterical’ illnesses, can have many severe symptoms such as painful cramps or paralysis but without any physical explanation. However, new research from the University of Cambridge and UCL (University College London) suggests that individuals with psychogenic disease, that is to say physical illness that stems from emotional or mental stresses, do have brains that function differently.
Psychogenic diseases may look very similar to illnesses caused by damage to nerves, the brain or the muscles, or similar to genetic diseases of the nervous system. However, unlike organic diseases, psychogenic diseases do not have any apparent physical cause, making them difficult to diagnose and even more difficult to treat.
‘The processes leading to these disorders are poorly understood, complex and highly variable. As a result, treatments are also complex, often lengthy and in many cases there is poor recovery. In order to improve treatment of these disorders, it is important to first understand the underlying mechanism,’ said Dr James Rowe from the University of Cambridge.
The study looked at people with either psychogenic or organic dystonia, as well as healthy people with no dystonia. Both types of dystonia caused painful and disabling muscle contractions affecting the leg. The organic patient group had a gene mutation (the DYT1 gene) that caused their dystonia. The psychogenic patients had the symptoms of dystonia but did not have any physical explanation for the disease, even after extensive investigations.
The scientists performed PET brain scans on the volunteers at UCL, to measure the blood flow and brain activity of both of the groups, and healthy volunteers. The participants were scanned with three different foot positions: resting, moving their foot, and holding their leg in a dystonic position. The electrical activity of the leg muscles was measured at the same time to determine which muscles were engaged during the scans.
The researchers found that the brain function of individuals with the psychogenic illness was not normal. The changes were, however, very different from the brains of individuals with the organic (genetic) disease.
Dr Anette Schrag, from UCL, said: ‘Finding abnormalities of brain function that are very different from those in the organic form of dystonia opens up a way for researchers to learn how psychological factors can, by changing brain function, lead to physical problems.’
Dr Rowe added: ‘What struck me was just how very different the abnormal brain function was in patients with the genetic and the psychogenic dystonia. Even more striking was that the differences were there all the time, whether the patients were resting or trying to move.’
Additionally, the researchers found that one part of the brain previously thought to indicate psychogenic disease is unreliable: abnormal activity of the prefrontal cortex was thought to be the hallmark of psychogenic diseases. In this study, the scientists showed that this abnormality is not unique to psychogenic disease, since activity was also present in the patients with the genetic cause of dystonia when they tried to move their foot.
Dr Arpan Mehta, from the University of Cambridge, said: ‘It is interesting that, despite the differences, both types of patient had one thing in common – a problem at the front of the brain. This area controls attention to our movements and although the abnormality is not unique to psychogenic dystonia, it is part of the problem.’
This type of illness is very common. Dr Schrag said: ‘One in six patients that see a neurologist has a psychogenic illness. They are as ill as someone with organic disease, but with a different cause and different treatment needs. Understanding these disorders, diagnosing them early and finding the right treatment are all clearly very important. We are hopeful that these results might help doctors and patients understand the mechanism leading to this disorder, and guide better treatments.’ University of Cambridge
New type of gene that regulates tumour suppressor PTEN identified
, /in E-News /by 3wmediaResearchers at Karolinska Institutet in Sweden have identified a new so-called pseudogene that regulates the tumour-suppressing PTEN gene. They hope that this pseudogene will be able to control PTEN to reverse the tumour process, make the cancer tumour more sensitive to chemotherapy and to prevent the development of resistance.
The development of tumours coincides with the activation of several cancer genes as well as the inactivation of other tumour-suppressing genes owing to damage to the DNA and to the fact that the cancer cells manage to switch off the transcription of tumour-suppressor genes. To identify what might be regulating this silencing, the researchers studied PTEN, one of the most commonly inactivated tumour-suppressor genes. It has long been believed that the switching-off process is irreversible, but the team has now shown that silenced PTEN genes in tumour cells can be ‘rescued’ and re-activated by a ‘pseudogene’, a type of gene that, unlike normal genes, does not encode an entire protein.
‘We identified a new non-protein encoding pseudogene, which determines whether the expression of PTEN is to be switched on or off,’ says research team member Per Johnsson, doctoral student at Karolinska Institutet’s Department of Oncology-Pathology. ‘What makes this case spectacular is that the gene only produces RNA, the protein’s template. It is this RNA that, through a sequence of mechanisms, regulates PTEN. Pseudogenes have been known about for many years, but it was thought that they were only junk material.’
No less than 98 per cent of human DNA consists of non-protein encoding genes (i.e. pseudogenes), and by studying these formerly neglected genes the researchers have begun to understand that they are very important and can have an effect without encoding proteins. Using model systems, the team has shown that the new pseudogene can control the expression of PTEN and make tumours more responsive to conventional chemotherapy.
‘This means that we might one day be able to re-programme cancer cells to proliferate less, become more normal, and that resistance to chemotherapy can hopefully be avoided,’ says Per Johnsson. ‘We also believe that our findings can be very important for the future development of cancer drugs. What we’re seeing here is just the tip of the iceberg. The human genome conceals no less than 15,000 or so pseudogenes, and it’s not unreasonable to think that many of them are relevant to diseases such as cancer.’ Karolinska Institutet
Clues to foetal alcohol risk
, /in E-News /by 3wmediaFoetal alcohol syndrome is the leading preventable cause of developmental disorders in developed countries. And foetal alcohol spectrum disorder (FASD), a range of alcohol-related birth defects that includes foetal alcohol syndrome, is thought to affect as many as 1 in 100 children born in the United States.
Any amount of alcohol consumed by the mother during pregnancy poses a risk of FASD, a condition that can include the distinct pattern of facial features and growth retardation associated with foetal alcohol syndrome as well as intellectual disabilities, speech and language delays, and poor social skills. But drinking can have radically different outcomes for different women and their babies. While twin studies have suggested a genetic component to susceptibility to FASD, researchers have had little success identifying who is at greatest risk or what genes are at play.
Research from Harvard Medical School and Veterans Affairs Boston Healthcare System sheds new light on this question, identifying for the first time a signalling pathway that might determine genetic susceptibility for the development of FASD.
‘Our work points to candidate genes for FASD susceptibility and identifies a path for the rational development of drugs that prevent ethanol neurotoxicity,’ said Michael Charness, chief of staff at VA Boston Healthcare System and HMS professor of neurology. ‘And importantly, identifying those mothers whose foetuses are most at risk could help providers better target intensive efforts at reducing drinking during pregnancy.’
The discovery also solves a riddle that had intrigued Charness and other researchers for nearly two decades. In 1996, Charness and colleagues discovered that alcohol disrupted the work of a human protein critical to foetal neural development—a major clue to the biological processes of FASD. The protein, L1, projects through the surface of a cell to help it adhere to its neighbours. When Charness and his team introduced the protein to a culture of mouse fibroblasts cells, L1 increased cell adhesion. Tellingly, the effect was erased in the presence of ethanol (beverage alcohol).
Charness and his team went on to develop multiple cell lines from that first culture, and that’s where they encountered the riddle: In some of those lines, alcohol disrupted L1’s adhesive effect, while in others it did not.
‘How could it be possible that a cell that expresses L1 is completely sensitive to alcohol, and others that express it are completely insensitive?’ asked Charness, who is also faculty associate dean for veterans hospital programs at HMS and assistant dean at Boston University School of Medicine.
Clearly, something else was affecting the protein’s sensitivity to alcohol — but what? Studies of twins provided one clue: Identical twins are more likely than fraternal twins to have the same diagnosis, positive or negative, for FASD. ‘That concordance suggests that there are modifying genes, susceptibility genes, that predispose to this condition,’ Charness said.
In the current study, Charness’ team and collaborators at the University of North Carolina School of Medicine in Chapel Hill conducted cell culture experiments to identify specific molecular events that contribute to the alcohol sensitivity of L1 adhesion molecules. They focused on what was happening to the L1 molecule inside a cell that could affect an event outside the cell such as disruption by alcohol.
‘We found that phosphorylation events that begin inside the cell can render the external portion of the L1 adhesion molecule more vulnerable to inhibition by alcohol,’ said Xiaowei Dou, HMS instructor in neurology in the Charness Lab and first author on the new study. ‘Phosphorylation was controlled by the enzyme ERK2, and occurred at a specific location on the internal portion of the L1molecule.’
Phosphorylation plays a significant role in a wide range of cellular processes. By adding a phosphate group to a protein or other molecule, phosphorylation turns many protein enzymes on and off, and thereby alters their function and activity.
The researchers also found that variations in ERK2 activity correlated with differences in L1 sensitivity to alcohol that they observed across cell lines and among different strains of mice. ‘Dou showed that he could take these cells that had been insensitive to alcohol for 13-14 years, and make them sensitive by ramping up the activity of this kinase’ Charness said.
These variations suggest that genes for ERK2 and the signalling molecules that regulate ERK2 activity might influence genetic susceptibility to FASD. Moreover, their identification of a specific locus that regulates the alcohol sensitivity of L1 might facilitate the rational design of drugs that block alcohol neurotoxicity.
‘The only thing this modification blocked was alcohol’s ability to inhibit L1,’ Charness said. ‘If you’re looking for a drug, ideally you’re looking for it to block the effects of the toxin without interfering with the target molecule of the toxin.’
The findings will also help guide an international consortium in its search for genes linked to families with fetal alcohol spectrum disorders. Harvard Medical School
UCLA study finds endocrine disorder is most common cause of elevated calcium levels
, /in E-News /by 3wmediaUnusually high calcium levels in the blood can almost always be traced to primary hyperparathyroidism, an under-treated, underreported condition that affects mainly women and the elderly, according to a new study by UCLA researchers.
The condition, which results from overactive parathyroid glands and includes symptoms of bone loss, depression and fatigue that may go undetected for years, is most often seen in African American women over the age of 50, the researchers discovered.
The study is one of the first to examine a large, racially and ethnically diverse population — in this case, one that was 65 percent non-white. Previous studies had focused on smaller, primarily Caucasian populations.
The four parathyroid glands, which are located in the neck, next to the thyroid, regulate the body’s calcium levels. When one is dysfunctional, it can cause major imbalances — for example, by releasing calcium from the bones and into the bloodstream. Over time, calcium loss from bones often leads to osteoporosis and fractures, and excessive calcium levels in the blood can cause kidney stones and worsening kidney function.
The UCLA researchers determined that hyperparathyroidism is the leading cause of high blood-calcium levels and is responsible for nearly 90 percent of all cases.
‘The findings suggest that hyperparathyroidism is the predominant cause of high calcium levels, so if patients find they have high calcium, they should also have their parathyroid hormone level checked,’ said the study’s lead author, Dr. Michael W. Yeh, an associate professor of surgery and endocrinology at the David Geffen School of Medicine at UCLA.
Hyperparathyroidism, which affects approximately 1 percent of the population, can be detected by measuring parathyroid hormone levels to determine if they are elevated or abnormal. UCLA
First single gene mutation shown to result in Type 1 diabetes
, /in E-News /by 3wmediaA JDRF-funded study out of Switzerland has shown that a single gene called SIRT1 may be involved in the development of type 1 diabetes (T1D) and other autoimmune diseases. The study represents the first demonstration of a mono-genetic defect leading to the onset of T1D.
The research began when Marc Donath, M.D., endocrinologist and researcher at the University Hospital Basel in Switzerland, discovered an interesting pattern of autoimmune disease within the family of one of his patients, a 26-year-old male who had recently been diagnosed with T1D. The patient showed an uncommonly strong family history of T1D; his sister, father, and paternal cousin had also been diagnosed earlier in their lives. Additionally, another family member had developed ulcerative colitis, also an autoimmune disease.
‘This pattern of inheritance was indicative of dominant genetic mutation, and we therefore decided to attempt to identify it,’ Dr. Donath said.
Four years of analysis using three different genotyping and sequencing techniques pointed to a mutation on the SIRT1 gene as the common indicator of autoimmune disease within the family. The SIRT1 gene plays a role in regulating metabolism and protecting against age-related disease. To gain more understanding of how this genetic change in SIRT1 leads to T1D, Dr. Donath and his team performed additional studies with animal models of T1D. When the mutant SIRT1 gene found in the families was expressed in beta cells, those beta cells generated more mediators that were destructive to them. Furthermore, knocking out the normal SIRT1 gene in mice resulted in their becoming more susceptible to diabetes with greatly increased islet destruction. Dr. Donath speculates that the beta cell impairment and death due to the SIRT1 mutation subsequently activates the immune system toward T1D.
‘The identification of a gene leading to type 1 diabetes could allow us to understand the mechanism responsible for the disease and may open up new treatment options,’ Dr. Donath explained.
Patricia Kilian, Ph.D., director of the Beta Cell Regeneration Program at JDRF, concurred, and said that the development is exciting for many reasons: ‘While the change in the genetic makeup within this family with type 1 diabetes is rare, the discovery of the role of the SIRT1 pathway in affecting beta cells could help scientists find ways to enhance beta cell survival and function in more common forms of the disease. This study also reinforces increasing evidence that abnormal beta cell function has a role in the development of type 1 diabetes, and that blocking or reversing early stages of beta cell dysfunction may help prevent or significantly delay the disease’s onset. Drug companies are already in the process of developing SIRT1 activators, which could eventually speed our ability to translate these new research findings into meaningful therapies for patients.’ JDRF
Improper protein digestion in neurons identified as a cause of familial Parkinson’s
, /in E-News /by 3wmediaResearchers at Columbia University Medical Center (CUMC), with collaborators at the Albert Einstein College of Medicine of Yeshiva University, have discovered how the most common genetic mutations in familial Parkinson’s disease damage brain cells. The mutations block an intracellular system that normally prevents a protein called alpha-synuclein from reaching toxic levels in dopamine-producing neurons. The findings suggest that interventions aimed at enhancing this digestive system, or preventing its disruption, may prove valuable in the prevention or treatment of Parkinson’s.
Parkinson’s disease is characterised by the formation of Lewy bodies (which are largely composed of alpha-synuclein) in dopamine neurons. In 1997, scientists discovered that a mutation in alpha-synuclein can lead to Lewy body formation. ‘But alpha-synuclein mutations occur in only a tiny percentage of Parkinson’s patients,’ said co-lead author David L. Sulzer, PhD, professor of neurology, pharmacology, and psychiatry at CUMC. ‘This meant that there must be something else that interfered with alpha-synuclein in people with Parkinson’s.’
Dr. Sulzer and his colleagues suspected that a gene called leucine-rich repeat kinase-2 (LRRK2) might be involved. LRRK2 mutations are the most common mutations to have been linked to Parkinson’s. The current study aimed to determine how these mutations might lead to the accumulation of alpha-synuclein.
‘We found that abnormal forms of LRRK2 protein disrupt a critical protein-degradation process in cells called chaperone-mediated autophagy,’ said Dr. Sulzer. ‘One of the proteins affected by this disruption is alpha-synuclein. As this protein starts to accumulate, it becomes toxic to neurons.’ Delving deeper, the researchers found that LRRK2 mutations interfere with LAMP-2A, a lysosome membrane receptor that plays a key role in lysosome function.
‘Now that we know this step that may be causing the disease in many patients, we can begin to develop drug treatments or genetic treatments that can enhance the digestion of these disease-triggering proteins, alpha-synuclein and LRRK2, or that remove alpha-synuclein,’ said Dr. Sulzer.
While LRRK2 mutations are the most common genetic cause of Parkinson’s, it is too early to tell whether these findings, and therapies that might stem from them, would apply to patients with non-familial Parkinson’s, the more common form of the disease. ‘Right now, all we can say is that it looks as though we’ve found a fundamental pathway that causes the buildup of alpha-synuclein in people with LRRK2 mutations and links these mutations to a common cause of the disease. We suspect that this pathway may be involved in many other Parkinson’s patients,’ said Dr. Sulzer.
The study involved mouse neurons in tissue culture from four different animal models, neurons from the brains of patients with Parkinson’s with LRRK2 mutations, and neurons derived from the skin cells of Parkinson’s patients via induced pluripotent stem (iPS) cell technology. All the lines of research confirmed the researchers’ discovery. Columbia University Medical Center