RESEARCH HIGHLIGHT 08 February 2023

The accumulation of misfolded α-synuclein is implicated in the pathogenesis of Parkinson disease (PD), spreading disease in a prion-like manner. Studies in animal models of PD have indicated that the internalization of pathologic α-synuclein by the affected neurons activates the cellular Abelson tyrosine kinase (c-Abl), which stimulates downstream processes affecting mitochondrial, endosomal and nuclear functions that collectively drive the death of neurons. Using an in silico design drug discovery approach with existing molecule scaffolds, Karuppagounder et al. report the development of the brain-penetrant orally bioavailable selective c-Abl inhibitor, IkT-148009, with a favourable toxicity profile. In mouse models of both inherited and sporadic PD, daily oral treatment with the c-Abl inhibitor beginning 4 weeks after disease initiation suppressed c-Abl activation to baseline levels or below and blocked neuronal degeneration, preserving 85% or more of dopaminergic neurons in the mouse brain. These effects correlated with recovery of motor function and reduction of accumulated pathologic α-synuclein. IkT-148009 has begun phase II trials to evaluate a clinical benefit in patients with treatment-naïve PD.

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doi: https://doi.org/10.1038/d41573-023-00024-w

References

Karuppagounder, S. et al. The c-Abl inhibitor IkT-148009 suppresses neurodegeneration in mouse models of heritable and sporadic Parkinson’s disease. Sci. Transl Med. 15, eabp9352 (2023)

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