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Funded Studies

Investigating the Effect of Parkin on Alpha-synuclein Propagation

Study Rationale:
Parkinson's disease (PD) has been demonstrated to start within the olfactory bulb (brain region that processes smell) and brain stem (brain region that controls involuntary functions) before spreading throughout the brain, causing the progressive loss of dopaminergic neurons. Recent findings point toward the possibility that alpha-synuclein is the reason for this progressive spreading. Alpha-synuclein is a protein that forms aggregates that appear to be prion-like (infectious agent) in nature, passing from neuron to neuron seeding new fibrils. A second PD-associated protein, Parkin, has been previously demonstrated to protect against the toxic effects of alpha-synuclein, making Parkin a promising therapeutic target to explore in the development of new PD therapies that can impede or impair this toxic spreading.

Hypothesis:
In this study, we will closely examine the relationship between Parkin function and activity with regard to the rate of alpha-synuclein spreading, to determine if promoting Parkin activity will protect against the propagation of toxic alpha-synuclein aggregates (protein clumps).

Study Design:
To test our hypothesis, we will use a combination of induced stem cell models ("man-made" stem cells that can become other cell types) and pre-clinical models to address two fundamental questions as follows: (1) How does the absence of Parkin affect the spreading of alpha-synuclein; (2) If we enhance Parkin activity, will this confer protection against the spreading of these aggregates?

Impact on Diagnosis/Treatment of Parkinson's disease:
If we find that switching on Parkin activity helps to reduce or to impede the spreading of alpha-synuclein, this would present a new therapeutic avenue to explore in PD therapies. Small molecules can be designed to activate Parkin and such molecules offer the potential to not only turn on the protective effects of Parkin in PD patients but to also directly impede the spreading of alpha-synuclein aggregates.

Next Steps for Development:
If Parkin activation proves to be protective against alpha-synuclein spreading, the next goals are to develop a set of small molecules that activate Parkin and prevent alpha-synuclein propagation. Candidate molecules demonstrated to be effective will be advanced into the next stages of development with the goal of identifying one or more candidate molecules for clinical trials.


Researchers

  • Thomas M. Durcan, PhD

    Montreal PQ Canada


  • Edward A. Fon, MD, FRCP(C)

    Montreal PQ Canada


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