Objective: In the present study we dissected the role of the first PD-associated mutations in RhoT1, the gene encoding for Miro1.

Background: Commonly involved pathogenic pathways are linked to mitochondrial dysfunction, e.g. increased oxidative stress, disruption of calcium homeostasis and decreased energy supply. A very important protein for mitochondrial distribution, quality control and maintenance is Miro1. To date Miro1 is not established as risk factor for PD.

Methods: In the present study we dissected the role of the first PD-associated mutations in RhoT1, using a comprehensive mutation screening of RhoT1 in German PD patients. Three mutations in RhoT1 have been identified in three PD patients with positive family history for PD. For analysis of mitochondrial phenotypes patient-derived fibroblasts were immortalized. As independent cell model served M17 cells with stable knock-down of endogenous RhoT1 and transiently overexpression of the RhoT1 mutant variants.

Results: Three mutations have been identified in three PD patients with positive family history for PD. Interestingly, the Miro1 protein amount was significantly reduced in Miro1-R>Q and Miro1-R>C mutant fibroblast lines compared to controls. Functional analysis revealed that mitochondrial mass was reduced in Miro1-R>C, but not in Miro1-R>Q fibroblasts. Furthermore, MnSOD was decreased in Miro1-R>C fibroblasts, although mitochondrial biogenesis was increased, as indicated by increased levels of PGC-1α. A similar phenotype with reduction of mitochondrial mass and MnSOD protein amount was also observed in neuroblastoma (M17) cells overexpressing Miro1-R>Q and Miro1-R>C. Additionally, respiratory activity was reduced in Miro1-R>Q fibroblasts compared to Miro1-R>C fibroblasts. Our findings suggest that Miro1-R>Q leads to impaired mitochondrial respiration. In contrast, Miro1-R>C fibroblasts showed increased respiration compared to Miro1-R>Q fibroblasts, despite citrate synthase activity was significantly reduced. Both alterations of respiratory activity lead to mitochondrial membrane hyperpolarization in Miro1-R>Q and Miro1-R>C fibroblasts.

Conclusions: Our study on functional consequences of variants in RhoT1 further underscores the relevance of mitochondrial function and dynamics in PD and indicates that RhoT1 might be a novel risk gene in PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/parkinsons-disease-associated-miro1-mutants-cause-mitochondrial-dysfunction/