The molecular causes of diseases such as Parkinson’s need to be understood as a first step towards combating them. University of Konstanz chemists working alongside Professor Malte Drescher recently succeeded in analysing what happens when selective mutations of the alpha-synuclein protein occur – a protein that is closely linked to Parkinson’s disease. In a complex series of experiments they examined what the effects were of changing a single amino acid in the protein. The physicochemists were able to prove how this tiny change disturbs the binding of alpha-synuclein to membranes. “We hope that the finding of this selectively defective membrane binding will help us to understand how Parkinson’s develops on a molecular level. Ultimately, this will facilitate the devising of therapeutic strategies,” outlines Julia Cattani, a doctoral student, who played a major role in the success of the research.
The human brain contains large quantities of the small alpha-synuclein protein. Its exact biological function is still unknown, yet it is closely linked to Parkinson’s disease; the protein “clumps together” in the nerve cells of Parkinson patients. Alpha-synuclein consists of a chain of 140 amino acids. In rare cases Parkinson’s disease is hereditary; where this occurs one of these 140 components has been replaced. Malte Drescher and his working group in the Department of Chemistry at the University of Konstanz have now found out the influence these selective changes in the protein sequence can have on the behaviour of alpha-synuclein. “We can show that the selective mutations disturb the membrane binding of alpha-synuclein on a local level,” explains Malte Drescher.
To find out more about the influence of selective mutations, the Konstanz-based chemists Dr Marta Robotta and Julia Cattani applied tiny magnetic probe molecules to various places on the alpha-synuclein protein. With the help of electron paramagnetic resonance spectroscopy – a procedure similar in method to magnetic resonance imaging (MRI) used in the medical field – the researchers were able to measure the rotation of these nanomagnets. At every residue at which alpha-synuclein binds to a membrane, the rotation slows down. In this way they were able to find out precisely when and where a binding to the membranes takes place – and when it does not. In the case of the exchanged amino acids the physicochemists from Konstanz discovered a disturbance of the membrane binding of alpha-synuclein – an important clue for the molecular context of Parkinson’s disease.
“We went to great lengths, performing over 200 spectroscopic experiments, the results of which we compared with our models by means of a specially developed simulation algorithm. The outcome certainly compensated our efforts,” says Julia Cattani. Project leader Malte Drescher believes that alongside the huge commitment of his staff, an important prerequisite for the success of the research was, above all, the environment of the Collaborative Research Centre (SFB) 969, “Chemical and biological principles of cellular proteostasis” which formed the basis for sponsoring the project: “By networking on an interdisciplinary level and discussing with colleagues we managed to solve the many problems we faced,” emphasises Malte Drescher.

University of Konstanz
www.uni-konstanz.de/en/university/news-and-media/current-announcements/news/news-in-detail/parkinson-auf-der-spur/

A gene previously identified as critical for tumour growth in many human cancers also maintains intestinal stem cells and encourages the growth of cells that support them, according to results of a study led by Johns Hopkins researchers. The finding adds to evidence for the intimate link between stem cells and cancer, and advances prospects for regenerative medicine and cancer treatments.
Study leader Linda M. S. Resar, M.D., professor of medicine, oncology and pathology at the Institute for Cellular Engineering at the Johns Hopkins University School of Medicine and a member of the Johns Hopkins Kimmel Cancer Center, has been studying genes in the high-mobility group (HMG) family for over two decades. Several years ago, while creating a genetically engineered mouse that expresses high levels of the mouse HMGA1 gene to investigate its role in leukaemia, Resar and her colleagues made the chance finding that the intestines of these animals were much larger and heavier than those of “wild-type” animals (or control mice that were not genetically modified). The mouse intestines were also riddled with polyps, abnormal growths projecting from the intestinal lining that can be precursors of cancer.  In fact, polyps in humans frequently progress to colon cancer, which is why they are removed during screening colonoscopies in people over 50 and others at risk for colon cancer.
To better understand how HMGA1 affected the rodents’ intestines, Resar and Lingling Xian, M.D., Ph.D., research associate at the Johns Hopkins University School of Medicine, and their colleagues examined the transgenic animals’ intestinal cells to determine which ones were expressing this gene. Several different experiments localized the active gene and its protein to stem cells buried within the crypts, or deep grooves in the intestinal lining.
After isolating these stem cells from both transgenic and wild-type mice, the researchers found that those carrying the HMGA1 transgene multiplied far more rapidly, forming identical daughter cells in a process called self-renewal, which is a defining property of all stem cells. These transgenic stem cells also readily created intestinal tissues called “organoids” in laboratory dishes. These organoids had more stem cells than those isolated from wild-type mice.
Further investigation, says Resar, showed that these unusual properties arise from the ability of HMGA1 to turn on several genes involved in the Wnt pathway, a network of proteins necessary for embryonic development and stem cell activity.
Stem cells do not function in isolation, explains Resar. They need a “niche” to survive and maintain an undifferentiated state. From the French word nicher, which means to build a nest, a niche is a nest-like compartment comprised of cells that secrete growth factors and other proteins that help stem cells survive. The niche also prevents stem cells from morphing into mature intestinal cells until new intestinal cells are needed.   Intestinal stem cells are particularly important because a new intestinal lining is generated about every 4-5 days.
Looking further into the intestinal crypts of both the transgenic and wild-type mice, the research team made what they consider a surprising finding: Not only was HMGA1 causing the stem cells themselves to self-renew or proliferate more rapidly in the transgenic animals, but it was also increasing the number of Paneth cells, a type of niche cell known to support intestinal stem cells. Additional experiments showed that the protein produced by HMGA1 activates another gene called Sox9, which is directly responsible for turning stem cells into Paneth cells.
“We suspected that HMGA1 might generate new stem cells, but we were extremely surprised that it also helps support these cells by building a niche,” Resar says. “We believe that our experiments provide the first example of a factor that both expands the intestinal stem cell compartment and builds a niche.”
Many genes that are involved in the growth and development of embryos or adult stem cells also play roles in cancer, Resar adds. After scanning the Cancer Genome Atlas, a database of genes expressed in human cancers, the research team discovered that the activity of both HMGA1 and SOX9 genes are tightly correlated in normal colon tissue, and both genes become highly overexpressed in colon cancer. “This tells us that the pathway turned on by HMGA1 in normal intestinal stem cells becomes disrupted and hyperactive in colon cancer,” Resar says.

John Hopkins Hospital
www.hopkinsmedicine.org/news/media/releases/single_gene_encourages_growth_of_intestinal_stem_cells_supporting_niche_cellsand_cancer_

Type 1 diabetes patients with elevated albumin in their urine had three times the risk of life-threatening kidney and cardiac disease as those with normal levels, according to researchers at the University of Colorado Anschutz Medical Campus.
The study, led by Dr. Petter Bjornstad, MD, of the Barbara Davis Center for Childhood Diabetes at CU Anschutz, looked at 38 males with type 1 diabetes and albumin in their urine and 38 diabetic males with normal albumin levels. The subjects were recruited across the country from the Type 1 Diabetes Exchange Biobank.
Albuminuria, or the presence of elevated albumin in the urine, is a marker for kidney disease. Bjornstad found that the copeptin was more than three times higher in patients with albuminuria. Copeptin is secreted along with arginine vasopressin or AVP from the pituitary gland and elevated levels appear to predict risk of cardiovascular mortality.
AVP is a hormone that regulates urination, though chronically high levels may cause kidney and vascular damage. But measuring AVP is extremely difficult due to its small size and short half-life. So researchers use copeptin as a surrogate. It is more stable, derived from the same molecule as AVP and can be more easily measured.
In this study, researchers found that the men with type 1 diabetes and albuminuria had significantly greater concentrations of copeptin compared to diabetic males with normal albumin levels.
“High levels of copeptin were associated with greater odds of albuminuria and impaired glomerular filtration rate which measures kidney function and stages of kidney disease,” Bjornstad said.
The findings, he said, could open the door to new ways of treating diabetic kidney disease and other illnesses. Specifically, a family of drugs called vaptans could be used to block excess vasopressin in these patients. “We think that vaptans or therapies targeting vasopressin can delay or stop the development of diabetic kidney disease,” Bjornstad said.
“There are clinical trials undergoing with vaptans in polycystic kidney disease, but to our knowledge no one is looking at vaptans and diabetic kidney disease yet.”
The study has important limitations. The sample size was small and its design prevents determination of causality. It also focused on men and may not apply to young people or women. But the findings support earlier research done by Bjornstad in the Coronary Artery Calcification in Type 1 Diabetes Study (CACTI.)
“We think these findings may have lifesaving implications for those with diabetic kidney and heart disease,” Bjornstad said.

University of Colorado Anschutz Medical Campus http://tinyurl.com/jfsnggz

A new study shows how errors in a specific gene can cause growth defects associated with a rare type of dwarfism.

During the study, an international team of scientists led by the University of Birmingham looked at genetic information from more than 250 people around the world with primordial dwarfism, a group of disorders characterised by short stature and an abnormally small head.

They found that 29 of the individuals had a defective version of a gene called DONSON.

Tests on cells growing in the laboratory revealed that this gene plays a crucial role in ensuring DNA is copied correctly when cells divide and grow.
Cells from patients with mutations in the DONSON gene had difficulty in efficiently replicating their DNA and protecting it from uncontrolled damage, ultimately leading to the growth defects typical of primordial dwarfism.

Most children with primordial dwarfism are not diagnosed until they are around three years old, and doctors are often unable to pinpoint the causes. This research raises the potential of more accurate diagnoses for patients with genetic microcephaly, in addition to providing an insight into how similar rare hereditary diseases are caused.

Professor Grant Stewart, from the Institute of Cancer and Genomic Sciences at the University of Birmingham, says: ‘Despite DNA replication being a process that is fundamental to life, there is still a lot we don’t know. This research sheds new light on the mechanisms underlying DNA replication, and the effect on human health when this process goes wrong.’

Professor Andrew Jackson, of the University of Edinburgh’s Institute for Genetics and Molecular Medicine, says:  ‘Identification of DONSON as a new microcephaly gene has given us new insights into how the genome is protected during DNA replication, and has only been possible through the close collaboration and contributions of clinicians and scientists from many countries around the world.’
Professor Christopher Mathew, from the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy’s and St Thomas’ and King’s College London, adds: ‘This is a good example of how unravelling the genetics of rare human disorders can provide profound insight into basic biological processes.’

NIHR Medical Research Institute www.guysandstthomasbrc.nihr.ac.uk/2017/02/14/research-gene-find-sheds-light-on-growth-defects-linked-to-dwarfism/

EKF Diagnostics, the global in vitro diagnostics company, announces that it is expanding the distribution of its Procalcitonin LiquiColor Test into Eastern Europe, Middle East and APAC regions. Procalcitonin (PCT) is a marker for bacterial infection and sepsis, a condition that has grown in awareness in recent years. PCT is now widely recognized as an important adjunct marker in sepsis diagnosis which aids in the differentiation between viral and bacterial infections. Sepsis can quickly develop into severe sepsis and septic shock – conditions associated with signs of end-stage organ damage and hypotension. At this stage, risk of death is high and increases drastically the longer the initiation of treatment is delayed. However, if a patient receives antimicrobial therapy within the first hour of diagnosis, their chances of survival are close to 80%. This short window is therefore often referred to as ’the golden hour.’ EKF’s Stanbio Chemistry PCT assay can be used in conjunction with other tests, to rapidly assess initial severity of sepsis within the golden hour.  As it provides quantitative results within ten minutes, it helps physicians to monitor treatment and track improvements over time. The test is CE-marked and will shortly receive FDA approval. It is an open-channel immunoturbidimetric assay that can run with multiple sample types, providing a cost effective solution for many hospital laboratories. “We have started to see significant interest in Asia Pacific for PCT. Here we are working closely with three major distributors covering the Philippines, Indonesia and Vietnam to introduce PCT into hospitals,” said Trevor McCarthy, EKF’s Sales Manager. “As awareness about the severity of sepsis and the importance of early detection grows, we anticipate more and more interest globally in this product. FDA approval will help us build our brand, both in the Asian market and further afield.”
www.ekfdiagnostics.com