Macroautophagy is a catabolic process that coordinates with lysosomes to degrade aggregation-prone proteins and damaged organelles. Loss of macroautophagy preferentially affects neuron viability and is associated with age-related neurodegeneration. We previously found that a-synuclein (a-syn) inhibits lysosomal function by blocking ykt6, a farnesyl-regulated SNARE protein that is essential for hydrolase trafficking in midbrain neurons. Using Parkinson’s disease (PD) patient iPSC-derived midbrain cultures, we find that chronic, endogenous accumulation of a-syn directly inhibits autophagosome-lysosome fusion by impairing ykt6-SNAP-29 complexes. In wild-type cultures, ykt6 depletion caused a near-complete block of autophagic flux, highlighting its critical role for autophagy in human iPSC-derived neurons. In PD, macroautophagy impairment was associated with increased farnesyltransferase (FTase) activity, and FTase inhibitors restored macroautophagic flux through promoting active forms of ykt6 in human cultures, and male and female mice. Our findings indicate that ykt6 mediates cellular clearance by coordinating autophagic-lysosomal fusion and hydrolase trafficking, and that macroautophagy impairment in PD can be rescued by FTase inhibitors.Significance Statement:The pathogenic mechanisms that lead to the death of neurons in Parkinson’s disease (PD) and Dementia with Lewy bodies (LBD) is currently unknown. Furthermore, disease modifying treatments for these diseases do not exist. Our study indicates that a cellular clearance pathway termed autophagy is impaired in patient-derived culture models of PD andin vivo. We identified a novel druggable target, a SNARE protein called ykt6, that rescues autophagyin vitroandin vivoupon blocking its farnesylation. Our work suggests that farnesyltransferase inhibitors may be useful therapies for PD and DLB through enhancing autophagic-lysosomal clearance of aggregated proteins.