| First Author | Peikert K | Year | 2021 |
| Journal | Acta Neuropathol Commun | Volume | 9 |
| Issue | 1 | Pages | 81 |
| PubMed ID | 33941276 | Mgi Jnum | J:346750 |
| Mgi Id | MGI:6811607 | Doi | 10.1186/s40478-021-01181-y |
| Citation | Peikert K, et al. (2021) Therapeutic targeting of Lyn kinase to treat chorea-acanthocytosis. Acta Neuropathol Commun 9(1):81 |
| abstractText | 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. |
