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.
Highlights
The ultra-rare neurodegenerative disease Chorea-Acanthocytosis (ChAc) with 1000–5000 cases worldwide is one of the core neuroacanthocytosis syndromes (NA) [26, 50, 70]
In isolated basal ganglia of Vps13a−/− mice, we found signs of neurodegeneration associated with (1) accumulation of Lyn, stabilized in high molecular weight complexes; (2) accumulation of autophagy related proteins; and (3) reduction in expression of beclin-1, a key initiator of autophagy, due to increased caspase 3 activity
The accumulation of active Src family kinases might be per se cytotoxic, contributing to impaired autophagy as reported in cancer cells [72, 73] The accumulation of At8- and At180-phosphorylated tau proteins and γ-synuclein as well as of polyubiquinated proteins in Vps13a−/− mouse basal ganglia is consistent with abnormal autophagy in the absence of chorein
Summary
The ultra-rare neurodegenerative disease Chorea-Acanthocytosis (ChAc) with 1000–5000 cases worldwide is one of the core neuroacanthocytosis syndromes (NA) [26, 50, 70]. Symptomatic treatment is currently available to modify the devastating disease course [71] despite a shortened life-span marked by considerable morbidity and compromised independent living. These clinical manifestations are accompanied by loss of striatal medium spiny neurons [38] and a distinctive cortical. Other members of the vacuolar protein sorting (Vps) family of proteins have been linked to more common neurodegenerative disorders such as Parkinson’s disease (PD) (Vps and Vps13c) and frontotemporal dementia (Vps4B) [34, 60]
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