Translational Neurodegeneration Section "Albrecht-Kossel", Department of Neurology, University Medical Center Rostock, University of Rostock, Gehlsheimer Straße 20, 18147, Rostock, Germany.
Division for Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, Dresden, Germany.
Acta Neuropathol Commun. 2021 May 3;9(1):81. doi: 10.1186/s40478-021-01181-y.
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.
舞蹈棘红细胞增多症（ChAc）是一种破坏性的、尚未被充分理解的、目前无法治疗的神经退行性疾病，由 VPS13A 突变引起。基于我们最近的研究表明，激活的 Lyn 酪氨酸激酶的积累是人类 ChAc 细胞的关键病理生理事件，我们利用 Vps13a 小鼠进行了研究，该小鼠模拟了人类 ChAc。通过蛋白质组学方法，我们发现 Vps13a 基底神经节中活性 Lyn、γ-突触核蛋白和磷酸化 tau 蛋白的积累，这是由于自噬受损导致神经炎症所致。Vps13a Lyn 双敲除小鼠的红细胞形态正常，基底神经节中的自噬得到改善。然后，我们在体内测试了 Lyn 的药理抑制剂：达沙替尼和尼罗替尼。达沙替尼未能穿过小鼠的血脑屏障（BBB），但更具特异性的 Lyn 激酶抑制剂尼罗替尼可以穿过 BBB。尼罗替尼改善了 Vps13a 的血液学和神经表型，改善了自噬并预防了神经炎症。我们的数据支持将尼罗替尼重新用于治疗 ChAc 患者的新治疗方案的提议。
