Translational neurodegenerationOct 30, 2026

Disordered proteins linked to problems with cell recycling acidity in brain diseases

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Nov 2, 2026

Abstract

Neurodegenerative diseases may be linked to defective vacuolar-type (H<sup>+</sup>)-ATPase (V-ATPase)⁺)-ATPase (V-ATPase)** function.

Accumulation of intrinsically disordered proteins (IDPs) is a characteristic of Alzheimer's disease, frontotemporal dementia, and Parkinson's disease.
IDPs disrupt neuronal homeostasis through toxic aggregation and impaired protein management, leading to neurodegeneration.
Defective V-ATPase function results in lysosomal deacidification and reduced ability to degrade cellular waste.
Pathological IDP species interact with V-ATPase, affecting its assembly and leading to further lysosomal dysfunction.
This dysfunction creates a cycle where impaired lysosomal degradation promotes the accumulation of IDPs.
Lysosomal dysfunction is identified as a common feature in neurodegeneration associated with IDPs and may serve as a therapeutic target.

Simplified

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.

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Disordered proteins linked to problems with cell recycling acidity in brain diseases

Abstract

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