Two proteins that share the ability to help cells deal with their trash appear to need each other to do their jobs and when they don’t connect, it appears to contribute to development of Parkinson’s disease, scientists report.

Much like a community’s network for garbage handling, cells also have garbage sites called lysosomes, where proteins, which are functioning badly because of age or other reasons, go for degradation and potential recycling, said Dr. Wen-Cheng Xiong, developmental neurobiologist and Weiss Research Professor at the Medical College of Georgia at Georgia Regents University.

Inside lysosomes, other proteins, called proteases, help cut up proteins that can no longer do their job and enable salvaging of things like precious amino acids. It’s a normal cell degradation process called autophagy that actually helps cells survive and is particularly important in cells such as neurons, which regenerate extremely slowly, said Xiong, corresponding author of the study.

Key to the process – and as scientists have shown, to each other – are two more proteins, VPS35 and Lamp2a. VPS35 is essential for retrieving membrane proteins vital to cell function. Levels naturally decrease with age, and mutations in the VPS35 gene have been found in patients with a rare form of Parkinson’s. VPS35 also is a critical part of a protein complex called a retromer, which has a major role in recycling inside cells. Lamp2a enables unfit proteins to be chewed up and degraded inside lysosomes.

If the two sound like a natural couple, scientists now have more evidence that they are. They have shown that without VPS35 to retrieve Lamp2a from the trash site for reuse, Lamp2a, or lysosomal-associated membrane protein 2, will be degraded and its vital function lost.

When the scientists generated VPS35-deficient mice, the mice exhibited Parkinson’s-like deficits, including impaired motor control. When they looked further, they found the lysosomes inside dopamine neurons, which are targets in Parkinson’s, didn’t function properly in the mice. In fact, without VPS35, the degradation of Lamp2a itself is accelerated. Consequently, yet another protein, alpha-synuclein, which is normally destroyed by Lamp2a, is increased. Alpha-synuclein is a major component of abnormal protein clumps, called Lewy bodies, found in the brains of patients with Parkinson’s.

“If alpha-synuclein is not degraded, it just accumulates. If VPS35 function is normal, we won’t see its accumulation,” Xiong said.

Conversely, when scientists increased expression of Lamp2a in the dopamine neurons of the VPS35-deficient mice, alpha-synuclein levels were reduced, a finding that further supports the linkage of the three proteins in the essential ability of the neurons to deal with undesirables in their lysosomes.

Without lamp2a, dopamine neurons essentially start producing more garbage rather than eliminating it. Recycling of valuables such as amino acids basically stops, and alpha-synuclein is free to roam to other places in the cell or other brain regions where it can damage still viable proteins.

The bottom line is dopamine neurons are lost instead of preserved. Brain scans document the empty spaces where neurons used to be in patients with neurodegenerative diseases such as Parkinson’s and Alzheimer’s. One of the many problems with treatment of these diseases is that by the time the empty spaces and sometimes the associated symptoms are apparent, much damage has occurred, Xiong said.

Putting these pieces together provides several new, early targets for disease intervention. “Everything is linked,” Xiong said. Medical College of Georgia at Georgia Regents University

Researchers at IRB Barcelona unravel a role for tumour suppressor genes in restricting the growth of neighbouring cell populations.

The study might have implications for understanding the early events of tumorigenesis and the selection of the tumour-initiating cells.
The healthy development of an organism depends on its tissues and organs growing to the right size, stopping when they need to, and maintaining stability in their form and function. Correct development depends on the availability of nutrients to the cells in their environment, a process that is tightly controlled by signalling mechanisms that occur within and between the cells that form these structures. Disruptions in this signalling can lead to unbalanced growth within a tissue or organ, and can give rise to conditions such as cancer.

The TOR and PI3K signalling pathways regulate tissue growth according to nutrient availability, and are frequently over-activated in human cancer. In the study published, Institute for Research in Biomedicine (IRB Barcelona) PhD student Ana Ferreira and Group Leader and ICREA Research Professor Marco Milán report that the over-activation of these two pathways not only causes the excess growth of cells and tissues, but also restrict the growth of neighbouring cell populations.

They present evidence that the proteoglycan Dally, a protein that is known to modulate the spreading, stability and activity of the growth-promoting signalling molecule called Dpp (in flies) or TGF-β (in humans), is regulated by these two pathways and mediates the effects on neighbouring populations. “They do so by competing for Dpp”, says Ana Ferreira, first author of the paper and funded by a PhD fellowship from Portugal’s Fundação para a Ciência e a Tecnologia.

‘PTEN, a gene that negatively regulates the PI3K pathway, is one of the most commonly lost tumour suppressors in human cancer. Understanding whether this pathway also affects TGF-β spreading in mammals may help us to gain insight into the early events of tumorigenesis and the selection of the tumour-initiating cells,’ she confirms.

‘Tumour initiating cells might be selected by their ability to compete for limiting growth factors and their capacity to restrict the growth of neighbouring cell populations,’ says Marco Milán, head of the Development and Growth Control Laboratory at IRB Barcelona. ‘Seventy percent of men with prostate cancer are estimated to have lost a copy of the PTEN gene at the time of diagnosis. It will be interesting to determine whether this mechanism, identified in fruit flies, is also active in humans.’ IRB Barcelona

ESC Guidelines published recommend DNA analysis as a fundamental component of post mortem assessment in young sudden death victims. Identification of a genetic cause helps to quickly diagnose and protect relatives. The Guidelines focus on preventing sudden cardiac death in patients with ventricular arrhythmias.

“For the first time these guidelines have incorporated the concept proposed by several consensus documents that DNA analysis should be a fundamental component of post mortem assessment in young sudden death victims,” said Professor Silvia Priori, Chairperson of the guidelines Task Force. “The molecular analysis helps to identify the presence of genetic diseases that can occur in a structurally normal heart and therefore cannot be identified during autopsy. Identification of a genetic cause as a substrate for a sudden death facilitates the early diagnosis of affected relatives and may help protect them through a personalised approach that spans from lifestyle modifications to the early use of therapies.” European Society of Cardiologists

Scientists have developed a blood test for breast cancer able to identify which patients will suffer a relapse after treatment, months before tumours are visible on hospital scans.

The test can uncover small numbers of residual cancer cells that have resisted therapy by detecting cancer DNA in the bloodstream.

Researchers at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust were able to track key mutations that cancer accumulates as it develops and spreads, without the need for invasive biopsy procedures.

They hope that by deciphering the DNA code found in blood samples, it should be possible to identify the particularly mutations likely to prove lethal to that patient – and tailor treatment accordingly.

The study is an important step towards use of ‘liquid biopsies’ to revolutionise breast cancer care – by changing the way cancer is monitored in the clinic and informing treatment decisions.

Researchers took tumour and blood samples from 55 breast cancer patients with early-stage disease who had received chemotherapy followed by surgery, and who had potentially been cured of their disease.

By monitoring patients with blood tests taken after surgery and then every six months in follow-up, the researchers were able to predict very accurately who would suffer a relapse.

Women who tested positive for circulating tumour DNA were at 12 times the risk of relapse of those who tested negative, and the return of their cancer was detected an average of 7.9 months before any visible signs emerged.

The researchers used a technique called ‘mutation tracking’ – developing a digital PCR test that was personalised to the mutations found in an individual patient’s cancer – to identify tumour DNA in the bloodstream.

Because the researchers at the ICR and The Royal Marsden were looking for mutations common to many types of breast cancers, they found the test could be applied to all breast cancer subtypes.

The research also showed how genetic mutations build up in the cancer as it develops over time, as the leftover cancer cells grow and spread.

This reinforces the importance of detecting recurrence early so patients can have treatment before the extra mutations emerge and make the disease harder to treat. Institute of Cancer Research

Many cancers include increased copies of the gene MET. But in which cases is MET driving the cancer and in which do these increased copies happen to ‘ride along’ with other molecular abnormalities that are the true cause of the disease? The answer influences whether a tumour will respond to drugs that inhibit MET, like crizotinib. A University of Colorado Cancer Center study sheds light on the best method to determine the threshold at which MET amplification becomes clinically relevant.

‘Generally, there are two ways that the number of copies of the MET gene can be increased: The tumour can make multiple copies of the entire chromosome on which it sits — chromosome 7 — or it can amplify just the MET region. In the first case, MET is unlikely to be the specific driver of the cancer’s biology, it may just be a ride along. But if the MET region is amplified separate from the rest of the chromosome, this would suggest that the MET gene is indeed the area of specific importance to the cancer,’ says Sinead Noonan, MD, investigator at the CU Cancer Center, senior thoracic oncology fellow at the CU School of Medicine, and the study’s first author.

The goal of the current study was to find evidence supporting the above hypothesis and to identify a group of MET-driven patients in which crizotinib would be effective.

To do so, Noonan worked with Marileila Garcia, PhD, CU Cancer Center investigator and professor of Oncology at the CU School of Medicine, who assessed the genetics of over 1,000 lung cancer patients. Using the low level criteria commonly used for defining an increase in MET copy number, independent of whether it was increased by increasing the overall number of copies of the chromosome or just that region of the chromosome, 14.4 percent of these samples were positive for MET copy number gain. The group then looked at another measure, comparing MET copy number to the number of chromosome 7 centromeres — the center point of the chromosome — which allowed them to see how specifically MET was amplified in comparison with the chromosome as a whole. When the low level criteria for defining an increase in MET copy number using the ratio of MET to centromere 7 was used, only 4.5 percent of these cases were positive.

Now the question was what ratio of MET to centromere 7, exactly, defined patients whose tumours were driven by this gene amplification and so would be most susceptible to MET inhibition via crizotinib.

‘There is almost always only one driver abnormality in any given tumour,’ Noonan says. But in 47 percent of the tumours defined by the minimal MET-to-centromere-7 ratio criteria, the group was able to identify other known genetic drivers, including mutations or gene rearrangements in EGFR, KRAS, BRAF, ALK, ERBB2, RET or ROS1.

‘Strikingly, as we looked at cases with higher and higher MET positivity, the degree of overlap with other known drivers decreased,’ Noonan says. In other words, as the MET-to-centromere-7 ratio increased, the group was less likely to find any other candidates for the cause of the cancer.

A group completely free from overlap with other known cancer drivers was only found in the group in which MET overbalanced centromere 7 by 5 times. Using the other common method of simply counting MET, independent of the ratio, it was impossible to find a group without additional known genetic driver.

‘I think these data really help to solidify MET-to-centromere ratio as the better measure for defining a lung cancer driven by MET copy number,’ says D. Ross Camidge, MD, PhD, Joyce Zeff Chair in Lung Cancer Research at the CU Cancer Center and the senior author of the study. ‘While the highest ratio only occurs in 0.34 percent of cases, it has clearly been associated with responses to crizotinib approaching 70 percent. However, responses have also been seen at lower ratios. Overall, if we look across all levels of MET-ratio positive cases but exclude those with other identifiable drivers we can identify a group representing 2.4 percent of adenocarcinomas which is ripe for further investigation as potential MET-sensitive subtypes of lung cancer.’ ScienceDaily