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This study examines how overexpression of the N\u2010terminally truncated Tau35 protein affects proteolytic pathways, including autophagy and endo\u2010lysosomal processes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>Using the Tau35 mouse model and SH\u2010SY5Y human neuroblastoma cells stably expressing Tau35 or full\u2010length tau, we assessed protein degradation and lysosomal function via Western blotting, proteomics of lysosome\u2010enriched brain fractions, cathepsin activity assays, endocytosis\/proteolysis assays, and live\u2010cell imaging using LysoTracker.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>We identified early endo\u2010lysosomal alterations associated with Tau35 expression, including increased endocytosis, disrupted autophagic flux, proteolytic impairment, and lysosomal motility defects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>These findings extend previous research by elucidating Tau35\u2010induced dysfunction in intracellular degradation systems and offer mechanistic insight into tauopathy progression. This work provides a foundation for developing targeted therapies to restore acidification, proteostasis, and lysosomal function in tauopathies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>\n                            <jats:bold>Tau35, an N\u2010terminally truncated tau fragment, disrupts proteolytic pathways<\/jats:bold>\n                            : We show that Tau35 overexpression leads to significant alterations in autophagy and endo\u2010lysosomal function.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            <jats:bold>Endo\u2010lysosomal dysfunction is an early pathological event<\/jats:bold>\n                            : Our findings demonstrate early\u2010stage increases in endocytosis, impaired proteolytic activity, altered autophagic flux, and disrupted lysosomal motility in Tau35\u2010expressing models.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            <jats:bold>\n                              <jats:italic>In vivo<\/jats:italic>\n                              and\n                              <jats:italic>in vitro<\/jats:italic>\n                              models confirm consistent pathogenic signatures\n                            <\/jats:bold>\n                            : Parallel studies in a Tau35 mouse model and SH\u2010SY5Y cells reveal converging cellular and molecular dysfunctions.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            <jats:bold>Lysosome\u2010enriched proteomics reveals novel pathway alterations<\/jats:bold>\n                            : Proteomic profiling of lysosomal fractions identifies Tau35\u2010specific protein dysregulation contributing to disease pathology.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            <jats:bold>Mechanistic insights into tauopathy progression<\/jats:bold>\n                            : These results provide a mechanistic understanding of how truncated tau species contribute to neuronal dysfunction, offering a rationale for targeting endo\u2010lysosomal pathways in therapeutic development.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  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