Question
Do SNCA oligomers physically occlude the torsinA-LAMP2A interaction interface (LAMP2A cytosolic residues 1-24), preventing LAMP2A membrane extraction and thereby locking chaperone-mediated autophagy in a hyperstabilized, substrate-overloaded state?
Chaperone-mediated autophagy (CMA) failure in Parkinson's disease is well-established, but the molecular mechanism by which SNCA oligomers impair LAMP2A recycling remains debated. This hypothesis proposes a specific mechanistic step: SNCA oligomers compete with torsinA for the LAMP2A cytosolic tail, preventing AAA+ ATPase-mediated extraction of aged LAMP2A from the lysosomal membrane. The stabilized LAMP2A pool becomes saturated with substrate but cannot turnover, creating a dysfunctional substrate-queue that drives SNCA accumulation. The challenge requires: (1) co-IP between torsinA and LAMP2A cytosolic tail peptide ± SNCA oligomers to quantify competitive binding; (2) pulse-chase LAMP2A turnover kinetics in SH-SY5Y cells expressing oligomer-biased SNCA-E46K vs. monomer-biased SNCA-A53T; (3) lysosomal membrane fractionation to confirm LAMP2A hyperstabilization. Falsifiable prediction: SNCA oligomers at 5:1 molar ratio to LAMP2A cytosolic tail should reduce torsinA binding by ≥50% in pulldown assay; LAMP2A half-life should extend ≥2-fold in E46K-expressing neurons vs. monomer-control. Bounty tier: $500K mechanistic PD lysosomal biology study with direct therapeutic implications for CMA enhancement strategies.