Axel CHEMLA

THE ROLE OF A PARKINSON’S DISEASE-ASSOCIATED RHOT1/MIRO1 VARIANT IN VITRO AND IN
VIVO

Objective:
The aim of this project is to identify disease-associated cellular phenotypes in Parkinson’s disease
(PD) patients carrying RHOT1/Miro1 mutations and discover potential new targets to correct
impaired Miro1 function.
Methods:
We first assessed mitochondrial function in iPSC-derived neurons from a PD patient carrying the
Miro1 R272Q mutation and the corresponding isogenic gene-corrected line. Age and gender-
matched controls were also included. Moreover, we generated a knock-in mouse model expressing
the mouse orthologue of the Miro1 R272Q mutation, i.e. Miro1 R285Q KI mouse, to evaluate the
impact of Miro1 deficiency on nigrostriatal pathway’s integrity in vivo.
Results:

We found that mitochondrial respiration was significantly impaired in Miro1 R272Q-mutant neurons
compared to healthy controls and the isogenic gene-corrected line. This phenotype was
accompanied by decreased mitochondrial membrane potential (MMP) and ATP levels, and by higher
accumulation of reactive oxygen species (ROS) in the Miro1 R272Q-mutant neurons compared to
both control lines.
In vivo, our findings demonstrated a significant reduction of dopaminergic neuron viability in the
substantia nigra pars compacta (SNpc) of old mice carrying the Miro1 R285Q mutation.
Conclusions:
We highlighted that the R272Q mutation causes alterations in energy metabolism of iPSC-derived
neurons in vitro. This is consistent with our former study, in which we observed an increase of
Mitochondria-ER contact sites and inhibition of mitochondrial clearance. We confirmed our
hypothesis that damaged mitochondria are not degraded, resulting in mitochondrial bioenergetics
impairments. Miro1 being a calcium sensor, among other roles, we will investigate the impact of the
R272Q mutation on calcium homeostasis.
In vivo, aging leads to dopaminergic neurons loss in the SNpc of mice expressing the human
orthologue R285Q, strengthening the involvement of the former Miro1 mutation in the pathogenesis
of PD.
Keywords: Parkinson’s disease, Miro1, Mitochondria, In vitro/In vivo

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