Fig. 1

Role of lysosomal acidification dysfunction in early neurodegenerative pathology. a Under normal physiological conditions, acidified lysosomes fuse with autophagosomes to form sufficiently acidified autolysosomes which can efficiently degrade accumulated cell debris and toxic protein aggregates. b Under pathological conditions, lysosomes with elevated pH either have no fusion with autophagosomes leading to no degradation, or fuse with autophagosomes to form poorly acidified autolysosomes which are inefficient in cellular degradation. c Poorly acidified lysosomes induce alterations from normal cellular and metabolic functions to early neurodegenerative pathology and could act as an early indicator of disease pathogenesis. d Pathogenesis of neurodegenerative diseases initiates with early pathology including increases of neuroinflammatory cytokines, activated glial cells, impaired neurotransmission, mitochondrial dysfunction, reactive oxygen species (ROS) production, and accumulation of pre-fibrillar, oligomeric toxic intrinsically disordered protein (IDP) aggregates due to inefficient cellular degradation by poorly acidified autolysosomes. e Late-stage neurodegeneration pathology includes the presence of toxic protein aggregates such as tau neurofibrillary tangles, Aβ plaques, and Lewy bodies with α-synuclein, as well as neuronal death. Schematics were created by BioRender.