| Title: |
Therapeutic targeting of Lyn kinase to treat chorea-acanthocytosis |
| Authors: |
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 |
| Contributors: |
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, Hanne; 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, Andrea; De Franceschi, Lucia |
| Publication Year: |
2021 |
| Collection: |
Università degli Studi di Verona: Catalogo dei Prodotti della Ricerca (IRIS) |
| Subject Terms: |
Basal ganglia; Cell signaling; Chorein; Lyn; Neurodegeneration |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
ELETTRONICO |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/33941276; info:eu-repo/semantics/altIdentifier/wos/WOS:000654817600002; volume:9; issue:81; firstpage:1; lastpage:15; numberofpages:15; journal:ACTA NEUROPATHOLOGICA COMMUNICATIONS; https://hdl.handle.net/11562/1042984 |
| DOI: |
10.1186/s40478-021-01181-y |
| Availability: |
https://hdl.handle.net/11562/1042984; https://doi.org/10.1186/s40478-021-01181-y |
| Rights: |
info:eu-repo/semantics/openAccess ; license:Creative commons ; license uri:http://creativecommons.org/licenses/by/3.0/it/ |
| Accession Number: |
edsbas.ABDB4955 |
| Database: |
BASE |