Until very recently, Parkinson’s had been thought a disease that starts in the brain, destroying motion centres and resulting in the tremors and loss of movement. New research shows the most common Parkinson’s gene mutation may change how immune cells react to generic infections like colds, which in turn trigger the inflammatory reaction in the brain that causes Parkinson’s. The research offers a new understanding of Parkinson’s disease.                                                     
“We know that brain cells called microglia cause the inflammation that ultimately destroys the area of the brain responsible for movement in Parkinson’s,” said Richard Smeyne, PhD, Director of the Jefferson Comprehensive Parkinson’s Disease and Movement Disorder Center at the Vickie and Jack Farber Institute for Neuroscience. “But it wasn’t clear how a common inherited mutation was involved in that process, and whether the mutation altered microglia.”
Together with Dr. Smeyne, first author Elena Kozina, PhD, looked at the mutant version of the LRRK2 gene (pronounced ‘lark’). Mutations in the LRRK2 gene are the most common cause of inherited Parkinson’s disease and are found in 40 percent of people of North African Arab descent and 18 percent of people of Ashkenazi Jewish descent with Parkinson’s. However there’s been controversy around the exact function of the LRRK2 gene in the brain.
“We know that gene mutation is not enough to cause the disease,” said Dr. Kozina, Post-Doctoral student at Jefferson.“We know that twins who both carry the mutation, won’t both necessarily develop Parkinson’s. A second ‘hit’ or initiating event is needed.”
Based on his earlier work showing that the flu might increase risk of Parkinson’s disease, Dr. Smeyne decided to investigate whether that second hit came from an infection. Suspecting that the LRRK2 mutations might be acting outside of the brain, the researchers used an agent — the outer shell of bacteria, called lippopolysaccharide (LPS) – that causes an immune reaction. LPS itself does not pass into the brain, nor do the immune cells it activates, which made it ideal for testing whether this second hit was acting directly in the brain.
When the researchers gave the bacterial fragments to the mice carrying the two most common LRRK2 gene mutations, the immune reaction became a “cytokine storm,” with inflammatory mediators rising to levels that 3-5 times higher than a normal reaction to LPS. These inflammatory mediators were produced by T and B immune cells expressing the LRRK2 mutation.
Despite the fact that LPS did not cross the blood-brain barrier, the researchers showed that the elevated cytokines were able to enter the brain, creating an environment that caused the microglia to activate pathologically and destroy the brain region involved in movement.
“Although more tests are needed to prove the link, as well as testing whether the same is true in humans, these findings give us a new way to think about how these mutations could cause Parkinson’s,” said Dr. Smeyne. “Although we can’t treat people with immunosuppressants their whole lives to prevent the disease, if this mechanism is confirmed, it’s possible that other interventions could be effective at reducing the chance of developing the disease.”
Thomas Jefferson Universitywww.jefferson.edu/university/news/2018/03/21/Parkinsons_gene_triggers_the_disease_from_outside_brain.html

Newly discovered gene mutations may help explain the cause of a disease that drastically impairs walking and thinking.
Mutations have been found in the bassoon (BSN) gene, which is involved with the central nervous system, in patients with symptoms similar to, but different from, a rare brain disorder called progressive supranuclear palsy (PSP).
PSP, a form of Parkinson’s disease, is often difficult to diagnose because it can affect people in different ways. Serious problems often include difficulty with walking and balance in addition to a decline in cognitive abilities such as frontal lobe dysfunction.
A team of Japanese researchers investigated patients whose symptoms resembled not only PSP but also Alzheimer’s disease. Despite similarities in the symptoms, detailed pathological analyses showed no resemblance to either disease, which prompted the team to further research the new disease’s underlying mechanism.
They first analysed the genomes of a Japanese family with several members displaying PSP-like symptoms. They identified a mutation in the BSN gene only in family members with symptoms. These individuals did not have mutations in the 52 other genes associated with PSP and other neurological disorders such as Alzheimer’s and Parkinson’s. This was the first time BSN gene is associated with a neurological disorder.
The researchers also detected three other mutations in the BSN gene in four out of 41 other patients displaying sporadic, or non-familial, PSP-like symptoms. None of the BSN mutations were detected in a random sample of 100 healthy individuals, underscoring the strong involvement of BSN mutations in the disease.
An autopsy done on one of the family members with the BSN mutation showed an accumulation of a protein called tau in the brain, which is not seen in a normal brain. The researchers believe that the BSN mutation is involved in the tau accumulation, which could cause the development of PSP-like symptoms. An experiment introducing a mutated rat BSN gene to cultured cells also suggested that the mutation causes the accumulation of tau. Communication between nerve fibres could also be affected, as BSN protein play a role in it.
ScienceDailywww.sciencedaily.com/releases/2018/03/180323093731.htm

There is as yet no cure for Alzheimer’s disease. It is often argued that progress in drug research has been hampered by the fact that the disease can only be diagnosed when it is too late for an effective intervention. Alzheimer’s disease is thought to begin long before patients show typical symptoms like memory loss. Scientists have now developed a blood test for Alzheimer’s disease and found that it can detect early indicators of the disease long before the first symptoms appear in patients. The blood test would thus offer an opportunity to identify those at risk and may thereby open the door to new avenues in drug discovery.
One of the hallmarks of Alzheimer’s disease is the accumulation of amyloid-β plaques in the patient’s brain. The blood test, developed by Klaus Gerwert and his team at Ruhr University Bochum, Germany, works by measuring the relative amounts of a pathological and a healthy form of amyloid-β in the blood. The pathological form is a misfolded version of this molecule and known to initiate the formation of toxic plaques in the brain. Toxic amyloid-β molecules start accumulating in the patients’ body 15-20 years before disease onset. In the present study, Gerwert and colleagues from Germany and Sweden addressed whether the blood test would be able to pick up indications of pathological amyloid-β in very early phases of the disease.
The researchers first focused on patients in the early, so called prodromal stages of the disease from the Swedish BioFINDER cohort conducted by Oskar Hanson. They found that the test reliably detected amyloid-β alterations in the blood of participants with mild cognitive impairment that also showed abnormal amyloid deposits in brain scans.
In a next step, Gerwert and colleagues investigated if their assay was able to detect blood changes well ahead of disease onset. They used data from the ESTHER cohort study, which Hermann Brenner started in 2000 at DKFZ, comparing blood samples of 65 participants that were later in the follow-up studies diagnosed with Alzheimer’s disease with 809 controls. The assay was able to detect signs of the disease on average eight years before diagnosis in individuals without clinical symptoms. It correctly identified those with the disease in almost 70% of the cases, while about 9% of true negative subjects would wrongly be detected as positive. The overall diagnostic accuracy was 86%.
Currently available diagnostic tools for Alzheimer’s disease either involve expensive positron emission tomography (PET) brain scans, or analyse samples of cerebrospinal fluid that are extracted via lumbar puncture. The researchers suggest that their blood test serves as a cheap and simple option to pre-select individuals from the general population for further testing by these more invasive and costly methods to exclude the falsely positive subjects.
EMBOwww.embo.org/news/press-releases/2018/a-new-blood-test-useful-to-detect-people-at-risk-of-developing-alzheimer-s-disease

Van Andel Research Institute (VARI) announced that the work of its scientists is featured in 27 papers focused on the output of The Cancer Genome Atlas (TCGA).
The findings are the result of a global scientific collaboration and mark the culmination of TCGA, a multi-institutional, joint effort between the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI) to develop a comprehensive scientific resource for better categorizing cancer. The more than decade-long initiative is the most in-depth undertaking of its kind, spanning 10,000 tumours across 33 cancer types.
“TCGA’s findings have greatly deepened our molecular understanding of the major cancer types,” said Peter W. Laird, Ph.D., a professor at VARI who led the DNA methylation analysis for TCGA Research Network and who is senior author on two of today’s papers. “It is our hope that these publications will serve as a guide for scientists who plan to harness TCGA’s robust data to develop new, more personalized methods of patient care.”
This research, which represents the project’s capstone, joins dozens of other papers that have been published since TCGA’s inception in 2005. Collectively, they provide a highly detailed description of molecular changes occurring in all major human cancers. The use of this molecular atlas is rapidly expanding, with more than 1,000 publications citing TCGA data in 2017 alone.
TCGA data may be accessed through the National Cancer Institute’s Genomic Data Commons Data Portal (portal.gdc.cancer.gov).
Along with Laird, VARI Assistant Professor Hui Shen, Ph.D., contributed to many of today’s papers, summaries of which may be found below. Shen also is one of six experts who authored retrospectives on TCGA’s legacy, which also were published.
A full list of papers may be found at www.cell.com/consortium/pancanceratlas.
Van Andel Institutewww.vai.org/news-release-4-5-2018/