Pathogenic LRRK2 R1441C mutation is associated with striatal alterations

LRRK2 mutations are associated with both familial and sporadic forms of Parkinsons disease (PD). Convergent evidence suggests that LRRK2 plays critical roles in regulating striatal function. Here, by using knock-in mouse lines that express the two most common LRRK2 pathogenic mutations (G2019S and R...

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Published inbioRxiv
Main Authors Xenias, Harry, Chen, Chuyu, Kang, Shuo, Cherian, Suraj, Situ, Xiaolei, Shanmugasundaram, Bharanidharan, Scesa, Giuseppe, Chan, C Savio, Parisiadou, Loukia
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 29.07.2020
Subjects
Dopamine
LRRK2 protein
Motor skill learning
Motor task performance
Movement disorders
Mutation
Neostriatum
Neurodegenerative diseases
Parkinson's disease
Rodents
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Summary:LRRK2 mutations are associated with both familial and sporadic forms of Parkinsons disease (PD). Convergent evidence suggests that LRRK2 plays critical roles in regulating striatal function. Here, by using knock-in mouse lines that express the two most common LRRK2 pathogenic mutations (G2019S and R1441C) we investigated how pathogenic LRRK2 mutations altered striatal physiology. We found that R1441C mice displayed a reduced nigrostriatal dopamine release and hypoexcitability in indirect-pathway striatal projection neurons. These alterations were associated with impaired striatal-dependent motor learning in the R1441C knock-in mice. In contrast, no detectable alterations were observed in the G2019S knock-in mice. In summary, our data argue that the impact of individual LRRK2 mutations cannot be simply generalized. Our findings have far-reaching implications for devising treatment strategies for PD patients. Competing Interest Statement The authors have declared no competing interest.
DOI:10.1101/2020.03.11.986455