Pubblicazioni

Autori:

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; Akgün, 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; De Franceschi, Lucia

Titolo:

Therapeutic targeting of Lyn kinase to treat chorea-acanthocytosis

Anno:

2021

Tipologia prodotto:

Articolo in Rivista

Tipologia ANVUR:

Articolo su rivista

Lingua:

Inglese

Formato:

Elettronico

Referee:

Sì

Nome rivista:

ACTA NEUROPATHOLOGICA COMMUNICATIONS

ISSN Rivista:

2051-5960

N° Volume:

9

Numero o Fascicolo:

81

Intervallo pagine:

1-15

Parole chiave:

Basal ganglia; Cell signaling; Chorein; Lyn; Neurodegeneration

Breve descrizione dei contenuti:

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.

Pagina Web:

https://doi.org/10.1186/s40478-021-01181-y

Id prodotto:

120961

Handle IRIS:

11562/1042984

ultima modifica:

15 novembre 2022

Citazione bibliografica:

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; Akgün, 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; De Franceschi, Lucia, Therapeutic targeting of Lyn kinase to treat chorea-acanthocytosis «ACTA NEUROPATHOLOGICA COMMUNICATIONS» , vol. 9 , n. 81 , 2021 , pp. 1-15

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