Initiation and propagation of alpha synuclein oligomers--Relevance for Parkinson s disease

from EU Research Autumn 2021

by Blazon Publishing and Media Ltd

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The alpha-synuclein protein is very abundant in the brain, and it can aggregate itself or with other proteins and form molecules called oligomers, some of which have toxic effects. We spoke to Professor Karin Danzer about her research into the mechanisms by which these oligomers propagate, which holds important implications for our understanding of Parkinson’s disease.

The alpha-synuclein protein is

present in large quantities in the brain, and over time it can start to aggregate and form different oligomers, some of which are toxic and are associated with the development of neurodegenerative disease. Currently based at the German Center for Neurodegenerative Diseases (DZNE), Professor Karin Danzer aims to shed new light on how these oligomers form and then propagate, building on earlier findings. “Previously it was thought that synuclein is just an intra-cellular protein, but then I and other researchers showed that it is also found extracellularly,” she outlines. Alpha synuclein is known to be involved in the pathology of Parkinson’s disease, and evidence suggests that extracellular alpha synuclein can have toxic effects. “It can promote seeding in other neurons, so that pathology is then being propagated from one area to another,” explains Prof Danzer.

This issue is central to Prof Danzer’s research, in which she and her colleagues have been

investigating the mechanisms by which alphasynuclein oligomers propagate. She and her group used a specific mouse model to gain deeper insights in this area. “We were able to express the protein in one area of the brain, and really measure these oligomers and follow them how they propagate,” explains Prof Danzer. One strand of research involves investigating, on a single cell level, the pathological consequence when an aggregate is transferred to a neighbouring cell. “What happens with the transcriptome of the ‘accepting’ cell? Why are certain populations more vulnerable than others?” continues Prof Danzer. “We can look at the transcriptome of a neuron which received extra-cellular synuclein from another cell that did not receive it. How does this look different from a cell expressing synuclein, for example?”

Researchers can then look to identify the consequences for cells if they take up extracellular synuclein. There are several different forms of synuclein, and it is still unclear which are toxic and which aren’t. “Many hypotheses

In vivo detection of alpha synuclein oligomers based on alpha Synuclein-split-venus (YFP) mouse model

have been put forward, suggesting that it is just the fibrils that are toxic, or proto-fibrills, or specific forms of oligomers,” says Prof Danzer. A clearer picture of which forms of alpha synuclein or oligomers are particularly toxic would represent a significant step forward in terms of guiding therapeutic interventions to treat Parkinson’s disease, believes Prof Danzer. “If the toxic species can be cleared, then this would be to another, and our understanding of different diseases often develops in parallel. With more of us expected to live longer neurodegenerative diseases are likely to affect more of the global population in future, underlining the wider importance of continued research. “We’re pursuing fundamental research into the mechanisms behind neurodegenerative disease,” says Prof Danzer.

If the toxic species can be cleared, then this would be a very nice therapeutic target. Researchers are tackling this problem now, using specific anti-bodies that detect certain forms of synuclein.

a very nice therapeutic target,” she explains. “Researchers are tackling this problem now, using specific anti-bodies that detect certain forms of synuclein.”

The focus of Prof Danzer’s attention is the mechanisms by which alpha-synuclein propagates however, and what these different forms of oligomers do in human cells, while she is also interested in the interaction between protein aggregation and the immune system in Parkinson’s disease. While Prof Danzer’s group are mainly investigating Parkinson’s disease and amyotrophic lateral sclerosis (ALS) , this research holds relevance to neurodegenerative diseases more widely. “There are many similarities between different neurodegenerative diseases. For example, in ALS, the aggregating protein is TDP-43. If we find a mechanism that’s related to a specific disease pathology, then we often investigate this mechanism in another disease,” she outlines.

A concept which first emerges in relation to a specific disease may prove to be relevant