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
Affiliations
- Kevin Peikert
- Translational Neurodegeneration Section “Albrecht-Kossel”, Department of Neurology, University Medical Center Rostock, University of Rostock
- Enrica Federti
- Department of Medicine, University of Verona
- Alessandro Matte
- Department of Medicine, University of Verona
- Gabriela Constantin
- Department of Medicine, University of Verona
- Enrica Caterina Pietronigro
- Department of Medicine, University of Verona
- Paolo Francesco Fabene
- Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona
- Paola Defilippi
- Department of Biotecnologie Molecolari E Scienze Per La Salute, University of Torino
- Emilia Turco
- Department of Biotecnologie Molecolari E Scienze Per La Salute, University of Torino
- Federico Del Gallo
- Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona
- Pietro Pucci
- Department of Chemical Sciences, University Federico II of Napoli
- Angela Amoresano
- Department of Chemical Sciences, University Federico II of Napoli
- Anna Illiano
- Department of Chemical Sciences, University Federico II of Napoli
- Flora Cozzolino
- Department of Chemical Sciences, University Federico II of Napoli
- Maria Monti
- Department of Chemical Sciences, University Federico II of Napoli
- Francesca Garello
- Molecular Imaging Center - Department of Molecular Biotechnology and Health Sciences, University of Torino
- Enzo Terreno
- Molecular Imaging Center - Department of Molecular Biotechnology and Health Sciences, University of Torino
- Seth Leo Alper
- Division of Nephrology, Beth Israel Deaconess Medical Center, Harvard Medical School
- Hannes Glaß
- Translational Neurodegeneration Section “Albrecht-Kossel”, Department of Neurology, University Medical Center Rostock, University of Rostock
- Lisann Pelzl
- Department of Physiology I, Eberhard Karl University
- Katja Akgün
- Department of Neurology, University Hospital Carl Gustav Carus, Technische Universität Dresden
- Tjalf Ziemssen
- Department of Neurology, University Hospital Carl Gustav Carus, Technische Universität Dresden
- Rainer Ordemann
- Medical Department I, University Hospital Carl Gustav Carus, Technische Universität Dresden
- Florian Lang
- Department of Physiology I, Eberhard Karl University
- Anna Maria Brunati
- Department of Molecular Medicine, University of Padua
- Elena Tibaldi
- Department of Molecular Medicine, University of Padua
- Immacolata Andolfo
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II
- Achille Iolascon
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II
- Giuseppe Bertini
- Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona
- Mario Buffelli
- Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona
- Carlo Zancanaro
- Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona
- Erika Lorenzetto
- Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona
- Angela Siciliano
- Department of Medicine, University of Verona
- Massimiliano Bonifacio
- Department of Medicine, University of Verona
- Adrian Danek
- Department of Neurology, Ludwig Maximilians University of Munich
- Ruth Helen Walker
- Department of Neurology, James J. Peters Veterans Affairs Medical Center
- Andreas Hermann
- Translational Neurodegeneration Section “Albrecht-Kossel”, Department of Neurology, University Medical Center Rostock, University of Rostock
- Lucia De Franceschi
- Department of Medicine, University of Verona
- DOI
- https://doi.org/10.1186/s40478-021-01181-y
- Journal volume & issue
-
Vol. 9,
no. 1
pp. 1 – 15
Abstract
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.
Keywords
