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Towards a first neuroprotective treatment against Huntington's disease

on the April 13, 2021

Cerebral palmitoylation as a new therapeutic target


Huntington disease (HD) damages the corticostriatal circuitry in large part by impairing transport of brain-derived neurotrophic factor (BDNF). We hypothesized that improving vesicular transport of BDNF could slow or prevent disease progression. 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 huntingtin-dependent trafficking. Using a synchronized trafficking assay and an HD network-on-a-chip, we found that increasing brain palmitoylation via ML348, which inhibits the palmitate-removing enzyme acyl-protein thioesterase 1 (APT1), restores axonal transport, synapse homeostasis, and survival signaling to wild-type levels without toxicity. In human HD induced pluripotent stem cell-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. APT1 and its inhibitor ML348 thus hold therapeutic interest for HD.

Référence : 

Increasing brain palmitoylation rescues behavior and neuropathology in Huntington disease mice
Science Advances 31 Mar 2021: Vol. 7, no. 14, eabb0799
Amandine Virlogeux, Chiara Scaramuzzino, Sophie Lenoir, Rémi Carpentier, Morgane
Louessard, Aurélie Genoux, Patricia Lino, Maria-Victoria Hinckelmann, Anselme L. Perrier, Sandrine Humbert and Frédéric Saudou.
DOI: 10.1126/sciadv.abb0799

Updated on April 13, 2021

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