LRRK2 inhibition does not impart protection from α-synuclein pathology and neuron death in non-transgenic mice

Acta Neuropathologica Communications
Michael X HendersonVirginia M Y Lee

Abstract

Mutations in leucine-rich repeat kinase 2 (LRRK2) are one of the most common causes of familial Parkinson's disease (PD). The most common mutations in the LRRK2 gene induce elevated kinase activity of the LRRK2 protein. Recent studies have also suggested that LRRK2 kinase activity may be elevated in idiopathic PD patients, even in the absence of LRRK2 mutations. LRRK2 is therefore a prime candidate for small molecule kinase inhibitor development. However, it is currently unknown how LRRK2 influences the underlying pathogenesis of PD and how LRRK2 might influence extant pathogenesis. To understand whether LRRK2 inhibition would show some benefit in the absence of LRRK2 mutations, we treated a preclinical mouse model of PD with the potent LRRK2 inhibitor MLi-2. The inhibitor was well-tolerated by mice and dramatically reduced LRRK2 kinase activity. However, LRRK2 inhibition did not reverse motor phenotypes, pathological α-synuclein accumulation or neuron loss. The current study suggests that LRRK2 is not necessary for α-synuclein pathogenesis in this mouse model of PD and that further studies are needed to assess the likely clinical benefit of LRRK2 inhibition in idiopathic PD.

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Citations

Jan 26, 2020·Nature Reviews. Neurology·Eduardo TolosaOlivier Rascol
Aug 1, 2020·Frontiers in Neuroscience·Dylan J Dues, Darren J Moore
Jun 12, 2020·Frontiers in Neuroscience·Marta MadureiraRichard Wade-Martins
Jan 11, 2020·Frontiers in Neuroscience·Federica AlbaneseMichele Morari
Feb 16, 2020·Acta Neuropathologica Communications·Chris McKinnonSuneil K Kalia
Sep 26, 2020·Bioscience Reports·Evy LobbestaelVeerle Baekelandt
Feb 18, 2021·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Anke Van der PerrenEvy Lobbestael
Apr 4, 2021·Cells·Jeswinder Sian-Hulsmann, Peter Riederer

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Methods Mentioned

BETA
GTPase
antisense oligonucleotides

Key Resources (RRID) Mentioned

AB_869973
AB_2336226
AB_477569
AB_91588
AB_2313606
AB_2313581
AB_2336819
AB_2336520
AB_2732035
AB_2721282

Software Mentioned

HALO
Studio
Image

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