Monthly Archives: February 2017

A new study suggests that a key to Parkinson’s disease may lie in the mitochondria, the powerhouses of the cell.

The results were published in Nature Communications.

Mitochondria, it seems, are not able to adapt to the effects of aging in people who get Parkinson’s disease. Mitochondria contain their own DNA, which tell them how to build their power generators. In this study, researchers compared brain cells from healthy aged persons to those of individuals with Parkinson’s disease.

The researchers discovered that brain cells of healthy persons are able to compensate for the age-induced damage by producing more DNA in their mitochondria. This protective mechanism is weakened in individuals with Parkinson’s disease, leading to a loss of the mitochondria’s healthy DNA population.

“I believe we have discovered an essential biological mechanism that normally preserves and protects the brain from aging related damage. Intriguingly, this mechanism appears to fail in persons with Parkinson’s disease, rendering their brain more vulnerable to the effects of aging,” said neurologist Dr Charalampos Tzoulis, who directed the study.

Paper: “Defective mitochondrial DNA homeostasis in the substantia nigra in Parkinson disease”
Reprinted from materials provided by the University of Bergen.

Patients who had a diagnosis of Parkinson’s disease (PD) with dementia (PDD) or dementia with Lewy bodies (DLB) and had higher levels of Alzheimer’s disease (AD) pathology in their donated post-mortem brains also had more severe symptoms of these Lewy body diseases (LBD) during their lives, compared to those whose brains had less AD pathology, according to new research. In particular, the degree of abnormal tau protein aggregations, indicative of AD, most strongly matched the clinical course of the LBD patients who showed evidence of dementia prior to their deaths, according to the study, which was published in The Lancet Neurology.

The team used post-mortem brain tissue donated by 213 patients with LBD and associated dementia, which was confirmed during autopsies to have alpha-synuclein pathology. They paired the tissue analysis with the patients’ detailed medical records. This unique study combined data from eight academic memory or movement disorder centers.

LBD is a family of related brain disorders made up of the clinical syndromes of PD, without or with dementia or DLB. LBD is associated with clumps of misshapened alpha-synuclein proteins. On the other hand, AD pathology is made up of clusters of the protein beta-amyloid called plaques and twisted strands of the protein tau, called tangles. Patients with LBD may have varying amounts of AD pathology, in addition to alpha-synuclein pathology.

Treatments directed at tau and amyloid-beta proteins are currently being tested in patients with Alzheimer’s disease. This study could help in selecting appropriate patients for trials of emerging therapies targeting these proteins singly or in combination with emerging therapies targeting alpha-synuclein protein in LBD.

The study suggests that Lewy body pathology may be the primary driver of disease seen in the patients; whereas, AD pathology has an impact on the overall course of disease.

None of the LBD patients had a clinical diagnosis of AD, but their post-mortem brain tissue revealed varying amounts of AD neuropathology. Post-mortem analysis of five brain regions per patient showed that they fell into one of four categories of AD pathology: 23 percent negligible or no AD, 26 percent had low-level, 21 percent intermediate, and 30 percent had high-level.

Increasing severity of AD pathology correlated with a shortened time from motor symptoms to the onset of dementia and death, with the most significant trends seen in the intermediate- and high-level AD groups compared to the low-level and no AD groups. Tau pathology, in particular, was the strongest predictor of a shorter time to dementia and death. AD pathology was also higher in patients who were older at the time of onset of motor symptoms and dementia.

The team also found that two relevant genetic variants in sequences of the patients’ DNA samples correlated with the amount of AD pathology. The frequency of a genetic variant in a gene coding for a protein involved in cholesterol metabolism (APOE, the most common risk factor for AD) was more frequent in patients who were in the intermediate or high AD pathology group compared to those in the low-level or no AD group. Interestingly, a variation in the gene for the protein GBA (a risk factor for LBD) was more frequent in patients without significant AD pathology. This gene is associated with LBD overall but not the subgroup with AD pathology.

In the brain, the enzyme GBA normally aids in the breakdown of worn out and misshapened proteins, such as alpha-synuclein. Together these findings suggest that genetic risk factors could influence the amount of AD pathology in LBD. Further understanding of the relationships between genetic risk factors and AD and alpha-synuclein pathology will help improve treatments for these disorders.

Paper: “Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective analysis”
Reprinted from materials provided by the Perelman School of Medicine at the University of Pennsylvania.

Researchers have identified a naturally occurring molecule that has the potential for preserving sites of communication between nerves and muscles in amyotrophic lateral sclerosis (ALS) and over the course of aging — as well as a molecule that interferes with this helpful process.

The discovery in mice has implications for patients with ALS, also known as Lou Gehrig’s disease.

Published in The Journal of Neuroscience, the research team describes a growth factor called FGFBP1, which is secreted by muscle fibers and maintains neuromuscular junctions — a critical type of synapse that allows the spinal cord to communicate with muscles, sending signals from the central nervous system to create movements.

In mouse models of ALS, a growth factor associated with the immune system, called TGF-beta, emerges and prevents muscles from secreting factors needed to maintain their connections with neurons.

“TGF-beta is upregulated in ALS and in turn blocks expression of FGFBP1, which is released by muscle fibers to preserve the integrity of the neuromuscular junction,” said Gregorio Valdez, who led the study. “The body is trying to help itself by generating more TGF-beta. Unfortunately, TGF-beta accumulates at the synapse where it blocks expression of FGFBP1, accelerating degeneration of the neuromuscular junction.”

FGFBP1 also gradually decreases during aging, but more precipitously in ALS, because TGF-beta accumulates at the synapse, according to the researchers.

Paper: “Muscle fibers secrete FGFBP1 to slow degeneration of neuromuscular synapses during aging and progression of ALS”
Reprinted from materials provided by Virginia Tech.



Researchers have discovered that mice with Huntington’s disease (HD) suffer defects in muscle maturation that may explain some symptoms of the disorder. The study, which was published in The Journal of General Physiology, suggests that HD is a disease of muscle tissue as well as a neurodegenerative disorder and that therapies targeting skeletal muscle may improve patients’ motor function.

HD is a progressive, and ultimately fatal, disorder caused by a mutation in the huntingtin gene that results in the production of defective huntingtin RNA and protein molecules that disrupt various cellular processes. The cognitive and psychiatric disturbances associated with HD, including memory loss and mood swings, are thought to result from the death of neurons in the striatum and cerebral cortex. But some of the disease’s motor symptoms, such as involuntary movements and muscle rigidity, could arise from the effects of mutant huntingtin in skeletal muscle.

The researchers previously found that mice with an early-onset form of HD showed skeletal muscle defects at late stages of the disease, particularly a decrease in the function of a protein called ClC-1, which conducts chloride ions into the cell. This appeared to be caused by defective processing of the messenger RNA encoding ClC-1 and contributed to muscle hyperexcitability, potentially causing some of the motor symptoms associated with HD. But the loss of ClC-1 function could simply be a late response to the death of neurons innervating skeletal muscle; whether the chloride channel is affected during the onset and progression of HD remained unclear.

In the new study, the researchers examined their HD model mice throughout the course of the disease. They found that the RNA encoding ClC-1 was misprocessed in both HD and control mice when they were young, but, as they grew older, only healthy animals were able to start correctly processing the RNA to produce functional ClC-1. Thus, even before their motor symptoms began to appear, ClC-1 function was reduced in the skeletal muscle of HD mice compared with healthy control animals.

This suggested that muscle maturation might be disrupted in HD mice. The reseachers found that HD mice expressed a form of the muscle motor protein myosin that is usually only produced in newborn mouse muscle. Moreover, they identified similar defects in muscle maturation in a different strain of mice with adult-onset HD.

The researchers say that their results could provide a new opportunity to improve patient care by targeting skeletal muscle tissue. In addition, researchers and clinicians may be able to use the skeletal muscle defects as biomarkers to track the progress of HD, a much easier task than examining patients’ brain tissue.


New details learned about a key cellular protein could lead to treatments for neurodegenerative diseases such as Parkinson’s, Huntington’s, Alzheimer’s, and amyotrophic lateral sclerosis (ALS).

At their root, these disorders are triggered by misbehaving proteins in the brain. The proteins misfold and accumulate in neurons, inflicting damage and eventually killing the cells. In a new study, researchers used a different protein, Nrf2, to restore levels of the disease-causing proteins to a normal, healthy range, thereby preventing cell death.

The researchers tested Nrf2 in two models of Parkinson’s disease: cells with mutations in the proteins LRRK2 and alpha-synuclein. By activating Nrf2, the researchers turned on several “house-cleaning” mechanisms in the cell to remove excess LRRK2 and alpha-synuclein.

In the study, published in the Proceedings of the National Academy of Sciences, the scientists used both rat neurons and human neurons created from induced pluripotent stem cells. They then programmed the neurons to express Nrf2 and either mutant LRRK2 or alpha-synuclein. Using a one-of-a-kind robotic microscope, the researchers tagged and tracked individual neurons over time to monitor their protein levels and overall health. They took thousands of images of the cells over the course of a week, measuring the development and demise of each one.

The scientists discovered that Nrf2 worked in different ways to help remove either mutant LRRK2 or alpha-synuclein from the cells. For mutant LRRK2, Nrf2 drove the protein to gather into incidental clumps that can remain in the cell without damaging it. For alpha-synuclein, Nrf2 accelerated the breakdown and clearance of the protein, reducing its levels in the cell.

The scientists say that Nrf2 itself may be difficult to target with a drug because it is involved in so many cellular processes, so they are now focusing on some of its downstream effects. They hope to identify other players in the protein regulation pathway that interact with Nrf2 to improve cell health and that may be easier to drug.

Paper: “Nrf2 mitigates LRRK2- and α-synuclein–induced neurodegeneration by modulating proteostasis”
Reprinted from materials provided by Gladstone Institutes.


Parkinson’s disease (PD) and other “synucleinopathies” are known to be linked to the misfolding of alpha-synuclein protein in neurons. Less clear is how this misfolding relates to the growing number of genes implicated in PD through analysis of human genetics. In two studies published in Cell Systems, researchers explain how they used a suite of novel biological and computational methods to shed light on the question.

To start, they created two ways to systematically map the footprint of alpha-synuclein within living cells. “In the first paper, we used powerful and unbiased genetic tools in the simple Baker’s yeast cell to identify 332 genes that impact the toxicity of alpha-synuclein,” explained Vikram Khurana, first and co-corresponding author on the studies. “Among them were multiple genes known to predispose individuals to Parkinson’s–so we show that various genetic forms of Parkinson’s are directly related to alpha-synuclein. Moreover, the results showed that many effects of alpha-synuclein have been conserved across a billion years of evolution from yeast to human,” he said.

“In the second paper, we created a spatial map of alpha-synuclein, cataloging all the proteins in living neurons that were in close proximity to the protein,” explained Chee Yeun Chung, who co-led both studies with Khurana. The mapping was achieved without disturbing the native environment of the neuron, by tagging alpha-synuclein with an enzyme–APEX–that allowed proteins less than 10 nanometers away from synuclein to be marked with a trackable fingerprint.

Remarkably, the maps derived from these two processes were closely related and converged on the same Parkinson’s genes and cellular processes. Whether in a yeast cell or in a neuron, alpha synuclein directly interfered with the rate of production of proteins in the cell, and the transport of proteins between cellular compartments.

Finally, the authors addressed two major challenges for any study that generates large data-sets of individual genes and proteins in model organisms like yeast: How to assemble the data into coherent maps? And how to integrate information across species, in this case from yeast to human?

Enter computational biologist Jian Peng: “First, we had to figure out much better methods to find human counterparts of yeast genes, and then we had to arrange the humanized set of genes in a meaningful way,” he explained. “The result was a new suite of computational tools that uses machine learning algorithms to visualize patterns and interaction networks based on genes that are highly conserved from yeast to humans–and then makes predictions about the additional genes that are part of the alpha-synuclein toxicity response in humans.”

This analysis produced networks that mapped out how alpha-synuclein is related to other Parkinson’s genes through well-defined molecular pathways. “We now have a system to look at how seemingly unrelated genes come together to cause Parkinson’s and how they are related to the protein that misfolds in this disease,” said Khurana. To confirm their work, the researchers generated neurons from Parkinson’s patients with different genetic forms of the disease. They showed that the molecular maps generated from their analyses allowed them to identify abnormalities shared among these distinct forms of Parkinson’s. Prior to this, there was no obvious molecular connection between the genes implicated in these varieties of PD. “We believe these methods could pave the way for developing patient-specific treatments in the future,” Khurana observed.

Papers: “In situ proteomic approaches connect alpha synuclein directly to endocytic trafficking and mRNA metabolism in neurons” and “Genome-scale networks link neurodegenerative disease genes to alpha-synuclein through specific molecular pathways.
Reprinted from materials provided by the Whitehead Institute.