Mitochondrial dysfunction and mitophagy defects in LRRK2-R1441C Parkinson's disease models

Williamson, Matthew G, Madureira, Marta, McGuinness, William, Heon-Roberts, Rachel, Mock, Elliot D, Naidoo, Kalina, Cramb, Kaitlyn M L, Caiazza, Maria-Claudia, Malpartida, Ana B, Lavelle, Martha, Savory, Katrina, Humble, Stewart W, Patterson, Ryan, Davis, John B, Connor-Robson, Natalie ORCID: https://orcid.org/0000-0001-8350-6928, Ryan, Brent J and Wade-Martins, Richard 2023. Mitochondrial dysfunction and mitophagy defects in LRRK2-R1441C Parkinson's disease models. Human Molecular Genetics 32 (18) , pp. 2808-2821. 10.1093/hmg/ddad102

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Abstract

Mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene have been identified as one of the most common genetic causes of Parkinson’s disease (PD). The LRRK2 PD-associated mutations LRRK2G2019S and LRRK2R1441C, located in the kinase domain and in the ROC-COR domain, respectively, have been demonstrated to impair mitochondrial function. Here, we sought to further our understanding of mitochondrial health and mitophagy by integrating data from LRRK2R1441C rat primary cortical and human induced pluripotent stem cell-derived dopamine (iPSC-DA) neuronal cultures as models of PD. We found that LRRK2R1441C neurons exhibit decreased mitochondrial membrane potential, impaired mitochondrial function and decreased basal mitophagy levels. Mitochondrial morphology was altered in LRRK2R1441C iPSC-DA but not in cortical neuronal cultures or aged striatal tissue, indicating a cell-type-specific phenotype. Additionally, LRRK2R1441C but not LRRK2G2019S neurons demonstrated decreased levels of the mitophagy marker pS65Ub in response to mitochondrial damage, which could disrupt degradation of damaged mitochondria. This impaired mitophagy activation and mitochondrial function were not corrected by the LRRK2 inhibitor MLi-2 in LRRK2R1441C iPSC-DA neuronal cultures. Furthermore, we demonstrate LRRK2 interaction with MIRO1, a protein necessary to stabilize and to anchor mitochondria for transport, occurs at mitochondria, in a genotype-independent manner. Despite this, we found that degradation of MIRO1 was impaired in LRRK2R1441C cultures upon induced mitochondrial damage, suggesting a divergent mechanism from the LRRK2G2019S mutation.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Oxford University Press
ISSN:	0964-6906
Date of First Compliant Deposit:	7 March 2024
Date of Acceptance:	14 June 2023
Last Modified:	15 Mar 2024 15:46
URI:	https://orca.cardiff.ac.uk/id/eprint/166972

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