LRRK2 inhibition does not impart protection from \u03b1-synuclein pathology and neuron death in non-transgenic mice

Virginia M Y Lee,Michael X Henderson,John Q Trojanowski,Modupe F Olufemi,Bin Zhang,Ian Mcgeary,Hannah Brown,Medha Sengupta

doi:10.1186/s40478-019-0679-5

Virginia M Y Lee, Michael X Henderson + Show 6 more

Open Access

https://doi.org/10.1186/s40478-019-0679-5

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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.

Highlights

Parkinson’s disease (PD) is the second most common neurodegenerative disease, after Alzheimer’s disease (AD), and the most common neurodegenerative movement disorder
MLi-2 is well tolerated and allows for relatively steady dosing in mice We have recently developed a mouse model of PD that does not rely on the overexpression of α-synuclein or neurotoxins, but rather injection of a small amount of pathogenic α-synuclein seeds in the dorsal striatum of wildtype mice [23]
There is increasing evidence that leucine-rich repeat kinase 2 (LRRK2) hyperactivation is present in both familial and sporadic PD, suggesting that LRRK2 plays a role in PD pathogenesis

Summary

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disease, after Alzheimer’s disease (AD), and the most common neurodegenerative movement disorder. Several of the early mutations identified, as well as whole gene duplications and triplications were in the gene encoding the synaptic protein α-synuclein [2, 7, 18, 20, 21, 27,28,29, 31, 38] This is the same protein that forms the characteristic pathology Lewy body aggregates seen in PD [15, 32, 33], suggesting that α-synuclein is a key protein in disease pathogenesis. One of the most commonly mutated genes in PD is leucine-rich repeat kinase 2 (LRRK2) [17] This large protein has scaffolding, GTPase and kinase domains. This finding would suggest that elevated LRRK2 kinase activity is playing a role in PD pathogenesis, and has led pharmaceutical companies to develop many highly selective and potent inhibitors of LRRK2 activity for the treatment of PD

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