Mechanisms of protein aggregation in Parkinson’s disease using zebrafish

How does protein aggregation spread throughout the nervous system in a zebrafish model of Parkinson's disease?

Project Abstract

Parkinson’s disease is a progressive neurodegenerative disease that affects 1% of the population over the age of 55. Current clinical treatments for Parkinson’s disease can only alleviate its early symptoms without halting overall disease progression, in part because the underlying molecular mechanisms of the disease are not well understood. One key step that occurs in the disease pathway is the abnormal aggregation of a small protein called α-synuclein. Over time, α-synuclein clumps together with lipids and other proteins, eventually forming larger scale aggregates known as Lewy bodies, classic hallmarks of the disease.

Despite the identification of α-synuclein as a key component of the disease pathway, the function of this protein, as well as how its aggregation progresses within neurons and potentially spreads to other neurons, is not known. In fact, some evidence suggests that Lewy bodies themselves may even be protective to neurons rather than toxic. Identifying α-synuclein’s clear role in Parkinson’s disease is crucial for determining whether and how it should be targeted in a new generation of treatments that could potentially halt disease progression.

In order to study how α-synuclein aggregation progresses through neurons and potentially through the nervous system, an in vivo vertebrate model is the most useful approach. One of the most powerful approaches to date is the use of mouse cranial windows (through the skull) to access and visualize the mouse brain. One key limitation, however, is that neither whole neurons nor whole brain regions can be visualized. In order to ask how α-synuclein aggregation spreads within and between neurons, an unobstructed view of the nervous system is paramount. Zebrafish provide a powerful new approach for studying α-synuclein aggregation in vivo. Zebrafish enable non-invasive imaging of the entire nervous system directly through the skin, present a straightforward system for in vivo drug screening, and are a powerful genetic tool, owing to their rapid generation time and ease of genetic manipulation. These tools will be crucial for studying how α-synuclein aggregation may progress through the brain in Parkinson’s disease.

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