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Therapeutic targeting of Lyn kinase to treat chorea-acanthocytosis.

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.

SUBMITTER: Peikert K

PROVIDER: S-EPMC8091687 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Therapeutic targeting of Lyn kinase to treat chorea-acanthocytosis.

Peikert Kevin K Federti Enrica E Matte Alessandro A Constantin Gabriela G Pietronigro Enrica Caterina EC Fabene Paolo Francesco PF Defilippi Paola P Turco Emilia E Del Gallo Federico F Pucci Pietro P Amoresano Angela A Illiano Anna A Cozzolino Flora F Monti Maria M Garello Francesca F Terreno Enzo E Alper Seth Leo SL Glaß Hannes H Pelzl Lisann L Akgün Katja K Ziemssen Tjalf T Ordemann Rainer R Lang Florian F Brunati Anna Maria AM Tibaldi Elena E Andolfo Immacolata I Iolascon Achille A Bertini Giuseppe G Buffelli Mario M Zancanaro Carlo C Lorenzetto Erika E Siciliano Angela A Bonifacio Massimiliano M Danek Adrian A Walker Ruth Helen RH Hermann Andreas A De Franceschi Lucia L

Acta neuropathologica communications 20210503 1

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<sup>-/-</sup> mice, which phenocopied human ChAc. Using proteomic approach, we found accumulation of active Lyn, γ-synuclein and phospho-tau proteins in Vps13a<sup>-/-</sup> basal gangli ...[more]

PMID: 33941276

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Project description:BackgroundVacuolar protein sorting 13 homolog A (VPS13A) disease, historically known as chorea-acanthocytosis, is a rare neurodegenerative disorder caused by biallelic mutations in VPS13A, usually resulting in reduced or absent levels of its protein product, VPS13A. VPS13A localizes to contact sites between subcellular organelles, consistent with its recently identified role in lipid transfer between membranes. Mutations are associated with neuronal loss in the striatum, most prominently in the caudate nucleus, and associated marked astrogliosis. There are no other known disease-specific cellular changes (eg, protein aggregation), but autopsy reports to date have been limited, often lacking genetic or biochemical diagnostic confirmation.ObjectiveThe goal of this study was to characterize neuropathological findings in the brains of seven patients with VPS13A disease (chorea-acanthocytosis).MethodsIn this study, we collected brain tissues and clinical data from seven cases of VPS13A for neuropathological analysis. The clinical diagnosis was confirmed by the presence of VPS13A mutations and/or immunoblot showing the loss or reduction of VPS13A protein. Tissues underwent routine, special, and immunohistochemical staining focused on neurodegeneration. Electron microscopy was performed in one case.ResultsGross examination showed severe striatal atrophy. Microscopically, there was neuronal loss and astrogliosis in affected regions. Luxol fast blue staining showed variable lipid accumulation with diverse morphology, which was further characterized by electron microscopy. In some cases, rare degenerating p62- and ubiquitin-positive cells were present in affected regions. Calcifications were present in four cases, being extensive in one.ConclusionsWe present the largest autopsy series of biochemically and genetically confirmed VPS13A disease and identify novel histopathological findings implicating abnormal lipid accumulation. © 2023 International Parkinson and Movement Disorder Society.

Dataset Information

Therapeutic targeting of Lyn kinase to treat chorea-acanthocytosis.

Publications

Therapeutic targeting of Lyn kinase to treat chorea-acanthocytosis.

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