TECPR2 DEFICIENCY INDUCES AXONAL AUTOPHAGY DYSREGULATION IN HEREDITARY SENSORY AND AUTONOMIC NEUROPATHY TYPE IX

Mutations in TECPR2 cause a rare neurological disorder classified as hereditary sensory and autonomic neuropathy type IX (HSAN9). Consistent with patient phenotypes, TECPR2-deficient mice exhibit sensory and motor deficits accompanied by neuroaxonal dystrophy in dorsal regions of the brainstem and spinal cord. At the cellular level, loss of TECPR2 leads to accumulation of autophagic structures in fibroblasts derived from HSAN9 patients, embryonic mouse fibroblasts, and nervous tissue from TECPR2 knockout mice, indicating impaired autophagic flux. Re-expression of full-length TECPR2 or its C-terminal domain rescues basal autophagosome accumulation in patient fibroblasts by promoting autophagosome–lysosome fusion.
Using dorsal root ganglion (DRG) neurons, we demonstrate that TECPR2 depletion induces bulbous axonal swellings enriched in autophagic vesicles and dysfunctional mitochondria. We further show that amphisome formation and axonal trafficking of autophagic vesicles are disrupted in TECPR2-/- neurons, and that autophagy induction exacerbates axonal retraction and triggers apoptotic neuronal death. In parallel, TECPR2 deficiency results in mitochondrial dysfunction, including membrane depolarization and elevated reactive oxygen species production. Mechanistically, the C-terminal domain of TECPR2 resolves axonal swellings and vesicular congestion by restoring amphisome formation and retrograde transport of autophagic vesicles in an LIR-dependent manner. Finally, behavioral analyses reveal previously unrecognized phenotypes in TECPR2-deficient mice, including increased anxiety, reduced light sensitivity, and altered auditory processing.