Therapeutic targeting of Lyn kinase to treat chorea-acanthocytosis.
Kevin PeikertEnrica FedertiAlessandro MatteGabriela ConstantinEnrica Caterina PietronigroPaolo Francesco FabenePaola DefilippiEmilia TurcoFederico Del GalloPietro PucciAngela AmoresanoAnna IllianoFlora CozzolinoMaria MontiFrancesca GarelloEnzo TerrenoSeth Leo AlperHannes GlaßLisann PelzlKatja AkgünTjalf ZiemssenRainer OrdemannFlorian LangAnna Maria BrunatiElena TibaldiImmacolata AndolfoAchille IolasconGiuseppe BertiniMario BuffelliCarlo ZancanaroErika LorenzettoAngela SicilianoMassimiliano BonifacioAdrian DanekRuth Helen WalkerAndreas HermannLucia De FranceschiPublished in: Acta neuropathologica communications (2021)
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.
Keyphrases
- chronic myeloid leukemia
- tyrosine kinase
- endothelial cells
- endoplasmic reticulum stress
- cell death
- induced apoptosis
- signaling pathway
- oxidative stress
- end stage renal disease
- blood brain barrier
- epidermal growth factor receptor
- traumatic brain injury
- high fat diet induced
- ejection fraction
- lipopolysaccharide induced
- newly diagnosed
- cerebral ischemia
- cognitive impairment
- induced pluripotent stem cells
- chronic kidney disease
- cell cycle arrest
- lps induced
- pluripotent stem cells
- prognostic factors
- inflammatory response
- peritoneal dialysis
- cell therapy
- electronic health record
- cancer therapy
- stem cells
- bone marrow
- wild type
- patient reported outcomes
- brain injury
- patient reported
- pi k akt
- skeletal muscle
- label free