Funded Studies
Study Rationale:
The pathological hallmark of Parkinson’s disease (PD) is the widespread accumulation of cellular inclusions, called Lewy Bodies, composed of clumps of improperly folded alpha-synuclein. Evidence suggests that misfolded alpha-synuclein can be taken up into healthy brain cells, where it seeds further accumulation of alpha-synuclein aggregates, ultimately leading to toxicity. If this observation holds true, preventing the uptake of toxic alpha-synuclein by healthy neurons could slow the progression of PD.
Hypothesis:
This study will examine whether blocking a receptor that neurons are thought to use to internalize alpha-synuclein prevents the uptake of the misfolded protein, the seeding and accumulation of toxic alpha-synuclein aggregates, and the degeneration of neurons.
Study Design:
We will first use a genetically engineered virus to shut down TM9SF2, the gene that encodes the alpha-synuclein receptor, in the part of pre-clinical brain that controls movement — one of the main brain circuits impacted in PD. This treatment should render neurons incapable of internalizing misfolded alpha-synuclein. Once this approach has been validated, we will inject misfolded alpha-synuclein aggregates into the brain to determine whether the reduction of alpha-synuclein uptake provides neuroprotection.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
If silencing TM9SF2 prevents the accumulation of pathological alpha-synuclein, targeting this receptor may prevent accumulation of alpha-synuclein in the brain of people with PD.
Next Steps for Development:
Positive findings in this study would support the development of novel pharmacologic strategies to target the TM9SF2 receptor in PD.