Dopaminergic neurodegeneration induced by Parkinson's disease-linked G2019S LRRK2 is dependent on kinase and GTPase activity

Jul 8, 2020Proceedings of the National Academy of Sciences of the United States of America

Dopamine cell loss caused by Parkinson’s-linked G2019S LRRK2 depends on its enzyme activities

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Abstract

induces the robust degeneration of substantia nigra dopaminergic neurons in a preclinical rat model of Parkinson's disease.

Mutations in LRRK2 are the most common cause of late-onset familial Parkinson's disease.
The G2019S mutation in LRRK2 influences both kinase and GTPase activities.
Pharmacological inhibition of LRRK2 kinase activity reduces neurodegeneration in this model.
Neuroprotection from kinase inhibition involves destabilization of human LRRK2 protein in the brain.
Normal GTPase activity is critical for G2019S LRRK2-induced neurodegeneration, with specific mutations providing neuroprotection through distinct mechanisms.

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Mutations in() are the most common cause of late-onset, autosomal-dominant familial Parkinson's disease (PD). LRRK2 functions as both a kinase and GTPase, and PD-linked mutations are known to influence both enzymatic activities. While PD-linked LRRK2 mutations can commonly induce neuronal damage in culture models, the mechanisms underlying these pathogenic effects remain uncertain. Rodent models containing familial LRRK2 mutations often lack robust PD-like neurodegenerative phenotypes. Here, we develop a robust preclinical model of PD in adult rats induced by the brain delivery of recombinant adenoviral vectors with neuronal-specific expression of human LRRK2 harboring the most common G2019S mutation. In this model, induces the robust degeneration of substantia nigra dopaminergic neurons, a pathological hallmark of PD. Introduction of a stable kinase-inactive mutation or administration of the selective kinase inhibitor, PF-360, attenuates neurodegeneration induced by G2019S LRRK2. Neuroprotection provided by pharmacological kinase inhibition is mediated by an unusual mechanism involving the robust destabilization of human LRRK2 protein in the brain relative to endogenous LRRK2. Our study further demonstrates that G2019S LRRK2-induced dopaminergic neurodegeneration critically requires normal GTPase activity, as hypothesis-testing mutations that increase GTP hydrolysis or impair GTP-binding activity provide neuroprotection although via distinct mechanisms. Taken together, our data demonstrate that G2019S LRRK2 induces neurodegeneration in vivo via a mechanism that is dependent on kinase and GTPase activity. Our study provides a robust rodent preclinical model of-linked PD and nominates kinase inhibition and modulation of GTPase activity as promising disease-modifying therapeutic targets. leucine-rich repeat kinase 2LRRK2LRRK2

Key numbers

36.9 ± 15.6%

Dopaminergic Neuron Loss

Loss of dopaminergic neurons in the substantia nigra after expression.

26.1 ± 3.1%

Neuronal Loss with PF-360

Neuronal loss in the substantia nigra with PF-360 treatment following expression.

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Dopaminergic neurodegeneration induced by Parkinson's disease-linked G2019S LRRK2 is dependent on kinase and GTPase activity

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