The pathological hallmark of Parkinson's disease (PD) is the widespread accumulation of cellular deposits (Lewy Bodies) comprised of clumps of a misfolded protein called alpha-synuclein. Evidence suggests that misfolded alpha-synuclein can be taken up into healthy neurons where it seeds further clumping of toxic alpha-synuclein. Prevention of the uptake of pathological alpha-synuclein into neurons may slow the progression of PD.
This study will examine whether blocking receptors that are believed to allow neurons to internalize misfolded alpha-synuclein can prevent the uptake of misfolded alpha-synuclein and the subsequent seeding and accumulation of toxic alpha-synuclein.
We will first use genetically-engineered viruses to silence the genes of two misfolded alpha-synuclein receptors (LAG3 and TM9SF2) in the nigrostriatal system - one of the main brain circuits impacted in PD - in pre-clinical models of PD. These neurons should be unable to internalize misfolded alpha-synuclein. Once the genetic silencing of the two receptors is validated, we will surgically inject misfolded alpha-synuclein to determine whether accumulation of pathological alpha-synuclein is affected.
Impact on Diagnosis/Treatment of Parkinson's disease:
If the accumulation of pathological alpha-synuclein is affected by silencing either receptor, targeting these receptors could prevent accumulation of alpha-synuclein in PD.
Next Steps for Development:
Positive findings from this study would support development of novel pharmacologic strategies to target these alpha-synuclein receptors.