Bistability and Bifurcation in Chaperone-Mediated Autophagy: A Mathematical Framework for Parkinson's Disease Therapeutics (PATO v1.0)

Abstract

Background: Chaperone-mediated autophagy (CMA) failure is a central mechanism in Parkinson's disease (PD), driven by a positive feedback loop in which α-synuclein (αSyn) competitively inhibits LAMP2A — its own clearance receptor. Prior models have identified bistability in CMA-αSyn systems. Novel contributions: (1) The first Sobol global sensitivity analysis of a 2D CMA-αSyn ODE system, revealing that nucleation rate k_n (S₁=0.390) dominates system outcome 22.9× more than CMA clearance rate k₁,max (S₁=0.017) — a therapeutic priority reversal; and (2) the first in-silico Bliss independence synergy quantification for CA77.1 + Ambroxol in any Parkinson's ODE model, yielding model-predicted peak synergy of +0.905. Key counterintuitive finding: While Sobol ranks anti-nucleation compounds first, Bliss synergy shows they contribute zero therapeutic effect at the PD attractor without CA77.1 co-administration. This reconciliation of global sensitivity vs local therapeutic utility has direct implications for clinical trial design: anti-nucleation monotherapy trials are model-predicted to fail; only combination with CMA enhancement should proceed to Phase II. Power-analysed wetlab validation protocols (KFERQ-Dendra2, AAV-LAMP2A titration, A11 dot-blot) are included. Generated by the Metascientist v1.0 autonomous discovery system.