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

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene are a common genetic cause of Parkinson's disease (PD).
• LRRK2 mutations, particularly LRRK2G2019S and LRRK2R1441C, are known to disrupt mitochondrial function.

Purpose of the Study:

• To investigate the impact of the LRRK2R1441C mutation on mitochondrial health and mitophagy in neuronal models of Parkinson's disease.
• To compare the effects of LRRK2R1441C with LRRK2G2019S and assess the efficacy of LRRK2 inhibition.

Main Methods:

• Utilized rat primary cortical and human induced pluripotent stem cell-derived dopaminergic (iPSC-DA) neuronal cultures expressing the LRRK2R1441C mutation.
• Assessed mitochondrial membrane potential, mitochondrial function, basal and activated mitophagy, mitochondrial morphology, and protein levels of mitophagy markers (pS65Ub) and MIRO1.
• Administered the LRRK2 inhibitor MLi-2 to evaluate its therapeutic potential.

Main Results:

• LRRK2R1441C neurons exhibited reduced mitochondrial membrane potential, impaired mitochondrial function, and decreased basal mitophagy.
• Mitochondrial morphology alterations were observed in iPSC-DA neurons but not cortical neurons, indicating cell-type specificity.
• LRRK2R1441C neurons showed reduced pS65Ub levels and impaired MIRO1 degradation upon mitochondrial damage, suggesting disrupted mitophagy activation and protein handling.
• The LRRK2 inhibitor MLi-2 did not restore mitophagy or mitochondrial function in LRRK2R1441C iPSC-DA neurons.

Conclusions:

• The LRRK2R1441C mutation impairs mitochondrial function and mitophagy in a cell-type-specific manner, distinct from LRRK2G2019S.
• Impaired degradation of MIRO1 in LRRK2R1441C neurons suggests a novel pathogenic mechanism.
• Current LRRK2 inhibition strategies may not fully address the mitochondrial dysfunction caused by the LRRK2R1441C mutation.