Author Archives: jpnd

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.

Older people who followed a Mediterranean diet retained more brain volume over a three-year period than those who did not follow the diet as closely, a new study published in Neurology shows. But contrary to earlier studies, eating more fish and less meat was not related to changes in the brain.

The Mediterranean diet includes large amounts of fruits, vegetables, olive oil, beans and cereal grains such as wheat and rice, moderate amounts of fish, dairy and wine, and limited red meat and poultry.

Researchers gathered information on the eating habits of 967 Scottish people around age 70 who did not have dementia. Of those people, 562 had an MRI brain scan around age 73 to measure overall brain volume, gray matter volume and thickness of the cortex, which is the outer layer of the brain. From that group, 401 people then returned for a second MRI at age 76. These measurements were compared to how closely participants followed the Mediterranean diet.

The participants varied in how closely their dietary habits followed the Mediterranean diet principles. People who didn’t follow as closely to the Mediterranean diet were more likely to have a higher loss of total brain volume over the three years than people who followed the diet more closely. The difference in diet explained 0.5 percent of the variation in total brain volume, an effect that was half the size of that due to normal aging.

The results were the same when researchers adjusted for other factors that could affect brain volume, such as age, education and having diabetes or high blood pressure.

There was no relationship between grey matter volume or cortical thickness and the Mediterranean diet.

Paper: „Mediterranean-type diet and brain structural change from 73 to 76 years in a Scottish cohort“
Reprinted from materials provided by the American Academy of Neurology.

Researchers have identified a link between Huntington’s disease and dysfunction of the subthalamic nucleus, a component of the basal ganglia, a group of brain structures critical for movement and impulse control.

Huntington’s disease is characterized by the progressive loss of nerve cells in the brain and affects approximately 1 in 10,000 people. This fatal disorder is caused by a hereditary defect in a single gene.

The study was published in the journal eLife.

Using mice genetically engineered to carry the Huntington’s disease gene, scientists discovered the electrical activity of the subthalamic nucleus was lost. Furthermore, impaired subthalamic activity was caused by anomalous receptor signaling, leading to defective energy metabolism and accumulation of damaging oxidants. The authors also found abnormalities in the subthalamic nucleus occur earlier than in other brain regions, and that subthalamic nucleus nerve cells progressively degenerate as the mice age, mirroring the human pathology of Huntington’s disease.

Currently, there is no cure for Huntington’s disease; treatment can only alleviate some of the symptoms. A better understanding of aberrant brain receptor signaling that leads to nerve cell dysfunction could reveal a target for therapy, according to the authors.

Paper: “Early dysfunction and progressive degeneration of the subthalamic nucleus in mouse models of Huntington’s disease”
Reprinted from materials provided by Northwestern Medicine.

The main changes in our brains as we get older are in the brain cells with a supporting role, called glial cells, scientists have found.

The surprising finding is published in the journal Cell Reports.

The researchers also found that the greatest changes in glial cells as we age are in the brain regions most often damaged by neurodegenerative disease, like Alzheimer’s and Parkinson’s.

The discovery suggests the interactions between glial cells and neuronal cells, the nerve cells active in mental function and forming memories, should be a focus of future dementia, Alzheimer’s and Parkinson’s disease research.

The scientists analysed brain tissue samples from 480 healthy people who were between 16 and 106 years old when they died. They looked at patterns of gene expression in neuron and glial cells in 10 different brain regions.

They used dedicated computational analyses – involving data mining and machine learning approaches – to examine the cell populations present in images scanned from stained brain sections. Each image would typically include hundreds of thousands of brain cells and is scanned in high resolution.

Most of the samples were provided by a UK brain bank, the Sudden Death MRC brain bank, based in Edinburgh, which stores post mortem brain tissue donated for research. This large resource, confirmed by samples from other brain banks, allowed the team to tell the story of how healthy human brains age.

The team’s findings and the new resource of data this research has generated provide an important foundation for future studies that apply a similar approach to learn more about neurodegenerative diseases.

Paper: „Major Shifts in Glial Regional Identity Are a Transcriptional Hallmark of Human Brain Aging“

Reprinted from materials provided by the Francis Crick Institute.

A new laboratory study provides clues on a particular pathway of alpha-synuclein diffusion.

Researchers have found that alpha-synuclein, a protein involved in a series of neurological disorders including Parkinson’s disease, is capable of travelling from brain to stomach and that it does so following a specific pathway. The study, carried out in rats, sheds new light on pathological processes that could underlie disease progression in humans. It was published in the journal Acta Neuropathologica.

Alpha-synuclein occurs naturally in the nervous system, where it plays an important role in synaptic function. However, in Parkinson’s disease, dementia with Lewy bodies and other neurodegenerative diseases termed “synucleinopathies”, this protein is accumulated within neurons, forming pathological aggregates. Distinct areas of the brain become progressively affected by this condition. The specific mechanisms and pathways involved in this widespread distribution of alpha-synuclein pathology remain to be fully elucidated. Clinical and experimental evidence suggests however that alpha-synuclein – or abnormal forms of it – could “jump” from one neuron to another and thus spread between anatomically interconnected regions.

Alpha-synuclein lesions have also been observed within neurons of the peripheral nervous system, such as those in the gastric wall. In some Parkinson’s patients, these lesions were detected at early disease stages.

With the help of a tailor-made viral vector the researchers triggered production of human alpha-synuclein in rats. The virus transferred the blueprint of the human alpha-synuclein gene specifically into neurons of the midbrain, which then began producing large quantities of the foreign protein, which is associated with some forms of Parkinson’s disease.

Tissue analysis by collaborators revealed that, after its midbrain expression, the protein was capable of reaching nerve endings in the gastric wall. Further work established the precise pathway used by human alpha-synuclein to complete its journey from the brain to the stomach. The protein first moved from the midbrain to the “medulla oblongata”, the lowest brainstem region; in the medulla oblongata, it was detected within neurons whose long fibers form the “vagus nerve”. Fibers of the vagus nerve connect the brain to a variety of internal organs; travelling within these fibers, human alpha-synuclein was ultimately able to reach the gastric wall about six months after its initial midbrain expression. Progressive accumulation of human alpha-synuclein within gastric nerve terminals was accompanied by evidence of neuronal damage.

Paper: „Brain-to-stomach transfer of α-synuclein via vagal preganglionic projections“
Reprinted from materials provided by DZNE.