Neurite Aggregation and Calcium Dysfunction in iPSC-Derived Sensory Neurons with Parkinson's Disease-Related LRRK2 G2019S Mutation

Summary

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most-common genetic determinants of Parkinson's disease (PD). The G2019S mutation is detected most frequently and is associated with increased kinase activity. Whereas G2019S mutant dopamine neurons exhibit neurite elongation deficits, the effect of G2019S on other neuronal subtypes is unknown. As PD patients also suffer from non-motor symptoms that may be unrelated to dopamine neuron loss, we used induced pluripotent stem cells (iPSCs) to assess morphological and functional properties of peripheral sensory neurons. LRRK2 G2019S iPSC-derived sensory neurons exhibited normal neurite length but had large microtubule-containing neurite aggregations. Additionally, LRRK2 G2019S iPSC-derived sensory neurons displayed altered calcium dynamics. Treatment with LRRK2 kinase inhibitors resulted in significant, but not complete, morphological and functional rescue. These data indicate a role for LRRK2 kinase activity in sensory neuron structure and function, which when disrupted, may lead to sensory neuron deficits in PD. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Authors Schwab AJ, Ebert AD
Journal Stem cell reports
Publication Date 2015 Dec 8;5(6):1039-1052
PubMed 26651604
PubMed Central PMC4682343
DOI 10.1016/j.stemcr.2015.11.004

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