Therapeutic targeting of Lyn kinase to treat chorea-acanthocytosis

Acta Neuropathol Commun. 2021 May 3;9(1):81. doi: 10.1186/s40478-021-01181-y.

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: Basal ganglia; Cell signaling; Chorein; Lyn; Neurodegeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dasatinib / administration & dosage
  • Drug Delivery Systems / methods*
  • Female
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neuroacanthocytosis / drug therapy*
  • Neuroacanthocytosis / enzymology*
  • Neuroacanthocytosis / genetics
  • Protein Kinase Inhibitors / administration & dosage*
  • Pyrimidines / administration & dosage
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / metabolism
  • src-Family Kinases / antagonists & inhibitors*
  • src-Family Kinases / genetics
  • src-Family Kinases / metabolism

Substances

  • Protein Kinase Inhibitors
  • Pyrimidines
  • Vesicular Transport Proteins
  • Vps13a protein, mouse
  • lyn protein-tyrosine kinase
  • src-Family Kinases
  • nilotinib
  • Dasatinib