Acta Neuropathologica Communications (May 2021)

Therapeutic targeting of Lyn kinase to treat chorea-acanthocytosis

  • Kevin Peikert,
  • Enrica Federti,
  • Alessandro Matte,
  • Gabriela Constantin,
  • Enrica Caterina Pietronigro,
  • Paolo Francesco Fabene,
  • Paola Defilippi,
  • Emilia Turco,
  • Federico Del Gallo,
  • Pietro Pucci,
  • Angela Amoresano,
  • Anna Illiano,
  • Flora Cozzolino,
  • Maria Monti,
  • Francesca Garello,
  • Enzo Terreno,
  • Seth Leo Alper,
  • Hannes Glaß,
  • Lisann Pelzl,
  • Katja Akgün,
  • Tjalf Ziemssen,
  • Rainer Ordemann,
  • Florian Lang,
  • Anna Maria Brunati,
  • Elena Tibaldi,
  • Immacolata Andolfo,
  • Achille Iolascon,
  • Giuseppe Bertini,
  • Mario Buffelli,
  • Carlo Zancanaro,
  • Erika Lorenzetto,
  • Angela Siciliano,
  • Massimiliano Bonifacio,
  • Adrian Danek,
  • Ruth Helen Walker,
  • Andreas Hermann,
  • Lucia De Franceschi

Journal volume & issue
Vol. 9, no. 1
pp. 1 – 15


Read online

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. 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.