The pathological roles of intrinsically disordered proteins in lysosomal acidification dysfunction in neurodegenerative diseases

Abstract Neurodegenerative diseases such as Alzheimer’s disease (AD), frontotemporal dementia (FTD), and Parkinson’s disease (PD) are characterized by the accumulation of intrinsically disordered proteins (IDPs), including amyloid-β (Aβ), tau, and α-synuclein (αSyn). These proteins disrupt neuronal homeostasis through toxic aggregation, impaired proteostasis, and progressive neurodegeneration, in part via dysfunction of the autophagy-lysosomal pathway (ALP). A central feature of this impairment is defective vacuolar-type (H + )-ATPase (V-ATPase) function, leading to lysosomal deacidification and reduced degradative capacity. Pathological IDP species converge on V-ATPase through direct interactions with its subunits or by perturbing its assembly, while also exerting protein-specific effects, including lysosomal membrane destabilization, impaired hydrolase activity, and disrupted endolysosomal trafficking. These combined mechanisms create a reciprocal relationship between lysosomal dysfunction and IDP accumulation, in which impaired lysosomal degradation further promotes the persistence and aggregation of pathological IDP species. This review synthesizes current insights into the molecular interplay between IDPs and lysosomal acidification across AD, FTD, and PD, and highlights how these processes contribute to disease progression. We further discuss emerging therapeutic strategies aimed at restoring lysosomal function. These findings underscore lysosomal dysfunction as a common feature of IDP-driven neurodegeneration and a potential therapeutic target across these disorders.