Proteomic analysis links truncated tau to lysosome motility, autophagy, and endo‐lysosomal dysfunction

Tau35, an N-terminally truncated tau fragment, disrupts proteolytic pathways: We show that Tau35 overexpression leads to significant alterations in autophagy and endo-lysosomal function. Endo-lysosomal dysfunction is an early pathological event: Our findings demonstrate early-stage increases in endocytosis, impaired proteolytic activity, altered autophagic flux, and disrupted lysosomal motility in Tau35-expressing models. In vivo and in vitro models confirm consistent pathogenic signatures: Parallel studies in a Tau35 mouse model and SH-SY5Y cells reveal converging cellular and molecular dysfunctions. Lysosome-enriched proteomics reveals novel pathway alterations: Proteomic profiling of lysosomal fractions identifies Tau35-specific protein dysregulation contributing to disease pathology. Mechanistic insights into tauopathy progression: These results provide a mechanistic understanding of how truncated tau species contribute to neuronal dysfunction, offering a rationale for targeting endo-lysosomal pathways in therapeutic development.