Therapeutic targeting of Lyn kinase to treat chorea-acanthocytosis.

ABSTRACT: Chorea-Acanthocytosis (ChAc) is a devastating, little understood, and currently untreatable neurodegenerative disease caused by VPS13A mutations. Based on our recent demonstration that accumulation of activated Lyn tyrosine kinase is a key pathophysiological event in human ChAc cells, we took advantage of Vps13a^-/- mice, which phenocopied human ChAc. Using proteomic approach, we found accumulation of active Lyn, γ-synuclein and phospho-tau proteins in Vps13a^-/- basal ganglia secondary to impaired autophagy leading to neuroinflammation. Mice double knockout Vps13a^-/- Lyn^-/- showed normalization of red cell morphology and improvement of autophagy in basal ganglia. We then in vivo tested pharmacologic inhibitors of Lyn: dasatinib and nilotinib. Dasa

SUBMITTER: Peikert K 

PROVIDER: S-EPMC8091687 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature