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Background Huntington Disease (HD) involves a complex cascade of pathogenic events, but central to its disruption of the cortico-striatal circuitry is impaired trafficking of Brain-Derived Neurotrophic Factor (BDNF). Aim We hypothesized that improving vesicular transport of BDNF could slow or prevent disease progression. Methods We therefore performed selective proteomic analysis of vesicles transported within corticostriatal projecting neurons followed by in silico screening and identified palmitoylation as a pathway that could restore defective HTT-dependent trafficking. Results Using a synchronized trafficking assay and a HD network-on-a-chip, we found that increasing brain palmitoylation via ML348, which inhibits the palmitate-removing enzyme APT1, restores axonal transport, synapse homeostasis, and survival signaling to WT levels without toxicity. In human HD iPSC-derived cortical neurons, ML348 increased BDNF trafficking. In HD knock-in mice, it efficiently crossed the blood-brain barrier to restore palmitoylation levels and reverse neuropathology, locomotor deficits, and anxio-depressive behaviors. Conclusion APT1 and its inhibitor ML348 thus hold therapeutic interest for HD. |
