TY - JOUR
T1 - Therapeutic targeting of Lyn kinase to treat chorea-acanthocytosis
AU - Peikert, Kevin
AU - Federti, Enrica
AU - Matte, Alessandro
AU - Constantin, Gabriela
AU - Pietronigro, Enrica Caterina
AU - Fabene, Paolo Francesco
AU - Defilippi, Paola
AU - Turco, Emilia
AU - Del Gallo, Federico
AU - Pucci, Pietro
AU - Amoresano, Angela
AU - Illiano, Anna
AU - Cozzolino, Flora
AU - Monti, Maria
AU - Garello, Francesca
AU - Terreno, Enzo
AU - Alper, Seth Leo
AU - Glaß, Hannes
AU - Pelzl, Lisann
AU - Akgün, Katja
AU - Ziemssen, Tjalf
AU - Ordemann, Rainer
AU - Lang, Florian
AU - Brunati, Anna Maria
AU - Tibaldi, Elena
AU - Andolfo, Immacolata
AU - Iolascon, Achille
AU - Bertini, Giuseppe
AU - Buffelli, Mario
AU - Zancanaro, Carlo
AU - Lorenzetto, Erika
AU - Siciliano, Angela
AU - Bonifacio, Massimiliano
AU - Danek, Adrian
AU - Walker, Ruth Helen
AU - Hermann, Andreas
AU - De Franceschi, Lucia
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
KW - Basal ganglia
KW - Cell signaling
KW - Chorein
KW - Lyn
KW - Neurodegeneration
UR - http://www.scopus.com/inward/record.url?scp=85105087773&partnerID=8YFLogxK
U2 - 10.1186/s40478-021-01181-y
DO - 10.1186/s40478-021-01181-y
M3 - Article
C2 - 33941276
AN - SCOPUS:85105087773
SN - 2051-5960
VL - 9
JO - Acta neuropathologica communications
JF - Acta neuropathologica communications
IS - 1
M1 - 81
ER -