Bardia Haghighirad*
Parkinson’s disease (PD) is a progressive neurodegenerative disorder and the second most prevalent cause of age-related disability worldwide. While existing therapies alleviate symptoms, they do not modify disease progression. Dysfunction of the autophagy–lysosome pathway (ALP), a principal component of cellular proteostasis, is significantly recognized as a key PD pathogenesis hallmark. ALP dysfunction contributes to the accumulation of misfolded proteins such as α-synuclein, defective organelle clearance, and neuronal vulnerability, with genetic forms of PD such as GBA1, SNCA, LRRK2, PRKN, PINK1, VPS35 converging on distinct yet overlapping disruptions of autophagic flux, lysosomal acidification, and mitophagy. Patient-derived induced pluripotent stem cells (iPSCs) have transformed PD research by enabling the generation of disease-modifying neural and glial lineages that retain the donor’s genetic background. These models have identified genotype-specific ALP dysfunctions, such as vesicular trafficking disruption in LRRK2 PD reduced glucocerebrosidase activity in GBA1 PD, and saturated flux inhibition in SNCA triplication models. iPSC-based systems have also shaped the evaluation of therapeutic interventions, including LRRK2 kinase inhibitors, GCase chaperones, TFEB activators, and chaperone-mediated autophagy enhancers, some of which in vitro studies have shown to partially restore ALP function. This review synthesizes key findings from patient-derived iPSC studies on ALP dysfunction in PD, highlighting mechanistic insights, therapeutic potentials, and methodological challenges. Standardization of differentiation protocols, adoption of consistent ALP assays, and integration of multi-disciplinary approaches are necessary to advance the translational potential of iPSC platforms for autophagy-targeted PD therapies.
