Therapeutic targeting of Lyn kinase to treat chorea-acanthocytosis

Peikert, Kevin; Federti, Enrica; Matte, Alessandro; Constantin, Gabriela; Pietronigro, Enrica Caterina; Fabene, Paolo Francesco; Defilippi, Paola; Turco, Emilia; Del Gallo, Federico; Pucci, Pietro; Amoresano, Angela; Illiano, Anna; Cozzolino, Flora; Monti, Maria; Garello, Francesca; Terreno, Enzo; Alper, Seth Leo; Glass, Hannes; Pelzl, Lisann; Akguen, Katja; Ziemssen, Tjalf; Ordemann, Rainer; Lang, Florian; Brunati, Anna Maria; Tibaldi, Elena; Andolfo, Immacolata; Iolascon, Achille; Bertini, Giuseppe; Buffelli, Mario; Zancanaro, Carlo; Lorenzetto, Erika; Siciliano, Angela; Bonifacio, Massimiliano; Danek, Adrian; Walker, Ruth Helen; Hermann, Andreas und De Franceschi, Lucia (2021): Therapeutic targeting of Lyn kinase to treat chorea-acanthocytosis. In: Acta Neuropathologica Communications, Bd. 9, Nr. 1, 81

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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2051-5960
• Sprache: Englisch