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, gamma-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. Dasatinib failed to cross the mouse brain blood barrier (BBB), but the more specific Lyn kinase inhibitor nilotinib, crosses the BBB. Nilotinib ameliorates both Vps13a(-/-) hematological and neurological phenotypes, improving autophagy and preventing neuroinflammation. Our data support the proposal to repurpose nilotinib as new therapeutic option for ChAc patients.
| Item Type: | Journal article |
|---|---|
| Faculties: | Medicine |
| Subjects: | 600 Technology > 610 Medicine and health |
| ISSN: | 2051-5960 |
| Language: | English |
| Item ID: | 101065 |
| Date Deposited: | 05. Jun 2023 15:36 |
| Last Modified: | 17. Oct 2023 15:06 |
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