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R1441C and G2019S LRRK2 knockin mice have distinct striatal molecular, physiological, and behavioral alterations

Xenias, Harry S., Chen, Chuyu, Kang, Shuo, Cherian, Suraj, Situ, Xiaolei, Shanmugasundaram, Bharanidharan, Liu, Guoxiang, Scesa, Giuseppe, Chan, C. Savio, Parisiadou, Loukia·2022·Communications Biology
DOI 10.1038/s42003-022-04136-8PMC PMC9649688

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Abstract

LRRK2 mutations are closely associated with Parkinson’s disease (PD). Convergent evidence suggests that LRRK2 regulates striatal function. Here, by using knock-in mouse lines expressing the two most common LRRK2 pathogenic mutations—G2019S and R1441C—we investigated how LRRK2 mutations altered striatal physiology. While we found that both R1441C and G2019S mice displayed reduced nigrostriatal dopamine release, hypoexcitability in indirect-pathway striatal projection neurons, and alterations associated with an impaired striatal-dependent motor learning were observed only in the R1441C mice. We also showed that increased synaptic PKA activities in the R1441C and not G2019S mice underlie the specific alterations in motor learning deficits in the R1441C mice. In summary, our data argue that LRRK2 mutations’ impact on the striatum cannot be simply generalized. Instead, alterations in electrochemical, electrophysiological, molecular, and behavioral levels were distinct between LRRK2 mutations. Our findings offer mechanistic insights for devising and optimizing treatment strategies for PD patients.

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Metadata

Authors
Xenias, H. S., Chen, C., Kang, S., Cherian, S., Situ, X., Shanmugasundaram, B., Liu, G., Scesa, G., Chan, C. S., & Parisiadou, L.
Venue
Communications Biology
Publisher
Springer Science and Business Media LLC
Published
2022-11-10
Volume
5
Issue
1
ISSN
2399-3642
DOI
10.1038/s42003-022-04136-8
PMC
PMC9649688
Cited by
32
References
8
Language
en
Licence
Funders
  • U.S. Department of Health & Human Services | National Institutes of Health (R01 NS097901)
  • Michael J. Fox Foundation for Parkinson’s Research (020600)

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