My PD Story

Preventing Alpha-synuclein Chain Reactions with Biometrical Precision

In Parkinson’s disease (PD), a protein called alpha-synuclein clumps into microscopic fiber-like structures in the brain, known as tangled fibrils. Eventually, this leads to a chain reaction that causes more alpha-synuclein to clump, causing affected neurons in the brain to break down and spread the fibrils to neighboring neurons. Ultimately, this impairs dopamine production, which is when Parkinson’s symptoms can become noticeable. Preventing this spread of alpha-synuclein fibrils is a promising target for new PD therapies. Jingxin Wang, PhD, recipient of a Parkinson’s Foundation 2023 Bill and Amy Gurley Impact Award, is studying how reducing alpha-synuclein levels overall can make a difference in PD progression.

Recent research has shown that alpha-synuclein fibrils only cause progressive disease when there is additional, normal alpha-synuclein present. With this in mind, Dr. Wang and his team at the University of Kansas have developed a new tool to reduce alpha-synuclein levels in neurons called ribonuclease targeting chimeras (RIBOTACs).

Parkinson's & The Role of RNA

Proteins are the molecular power tools of the cell, each designed for specific jobs. Sometimes, proteins get bent or broken, causing damage.

In Parkinson’s disease, the protein alpha-synuclein breaks in a way that causes other alpha-synuclein proteins to break in a chain reaction. This happens in the brain and its damage leads to the symptoms associated with PD.

If proteins are tools, RNAs are the blueprints; RNA molecules are used to make proteins in the cell. The theory tested by this research is whether the alpha-synuclein chain reaction can be stopped by erasing all those RNA blueprints and stopping more alpha-synuclein from being made. If proven true, this intervention could ultimately be used to stop PD from spreading.

RIBOTACs are molecules with two “arms” — one that grabs alpha-synuclein RNA and another that helps break that RNA down. RNA is required for making proteins, so using this new method, RIBOTACs can reduce the amount of alpha-synuclein available, thereby preventing clumping.

Dr. Wang and his collaborator at Johns Hopkins University, Dr. Xiaobo Mao, will test the effectiveness of these RIBOTACs in mammals by injecting them into mouse neurons to measure how those RNA and protein levels are affected. A week later he will inject alpha-synuclein fibrils into the neurons to test the RIBOTACs ability to prevent the spreading and clumping of alpha-synuclein. These studies will evaluate if RIBOTACs have the potential to reduce or prevent PD progression by blocking fibril chain reactions.

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