What is Alpha-synuclein?

Alpha-synuclein is a protein which is abundant in the human brain. It is also present in other body tissues notably the heart, muscle and gut. In the brain it tends to be concentrated near the tips of neurones in association with synaptic vesicles which are responsible for the release of chemicals between neurons - neurotransmission. Although the main functions of alpha-synuclein are still not fully understood, we do know it seems to be associated with the regulation of the release of dopamine, the neurotransmitter that is critical in PD as it is involved in controlling the start and stop of voluntary and involuntary movements. Alpha-synuclein is also involved in movements of chemicals and their production inside the nerve cell (neuron). Recently there has been some evidence that alpha-synuclein aggregates could also spread from cell to cell and promote the aggregation of proteins in the newly infected cells.

Alpha-synuclein is normally a wavy-like structure and in Parkinson's, the alpha-synuclein protein misfolds forming a toxic clump or appregate. During this process the early aggregations are very reactive and it is believed cause damage to cellular components. They also go on to accumulate in large masses termed 'Lewy bodies' and these clumps are now associated with brain cell death; the process involved in the aggregation of these misfolded proteins may be a trigger for PD. It is hard to say exactly what prompts the start of the damaging process. Alpha-synuclein, like all other proteins produced in the cells of the body is subject to regulation and recycling and sometimes it is the failure of this process that may lead to aggregation. Also, for a very small subset of people with Parkinson's, hereditary variability in the alpha-synuclein gene contributes to developing the disease.

Although scientists do not know exactly what causes the protein to misfold and clump together, many believe that if we find a way to prevent its accumulation or reduce alpha-synuclein gene expression or promote its removal and or recycling , we may be able to stop and potentially reverse the damage these deposits may cause to the brain. It is not surprising then that alpha-synuclein has now become a major target for potential PD therapies.

Why is Alpha-synuclein of interest to CPT?

Research findings are still in the early phase but we are optimistic that this research focus is exciting! CPT has and is funding several different target approaches - some are directed at how much alpha-synuclein is made; some, how to restore normal distribution in neurons; and how to stop it from spreading through neurons in the brain. For all of these, the goal is the same: to slow or stop PD. The findings from these research projects will, it is hoped, ultimately support the development of PD therapies which could potentially prevent or delay the onset, or halt or slow its progression.

Our Projects:

- Professor Maria Spillantini - a-synuclein aggregation
- Professor Roger Barker - RVG9R-p137
- Dr Javier Alegre Abarrátegui – LRKK2
- Flint Beal- DPufa

- Dr Richard Gordon - inflammasome-driven pathology in PD - alpha-synuclein

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