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Abstract #105770 Published in IGR 23-3

Restoration of mitochondria axonal transport by adaptor Disc1 supplementation prevents neurodegeneration and rescues visual function

Quintero H; Shiga Y; Belforte N; Alarcon-Martinez L; El Hajji S; Villafranca-Baughman D; Dotigny F; Di Polo A
Cell reports 2022; 40: 111324

See also comment(s) by Makoto AiharaKevin Park

Deficits in mitochondrial transport are a common feature of neurodegenerative diseases. We investigated whether loss of components of the mitochondrial transport machinery impinge directly on metabolic stress, neuronal death, and circuit dysfunction. Using multiphoton microscope live imaging, we showed that ocular hypertension, a major risk factor in glaucoma, disrupts mitochondria anterograde axonal transport leading to energy decline in vulnerable neurons. Gene- and protein-expression analysis revealed loss of the adaptor disrupted in schizophrenia 1 (Disc1) in retinal neurons subjected to high intraocular pressure. Disc1 gene delivery was sufficient to rescue anterograde transport and replenish axonal mitochondria. A genetically encoded ATP sensor combined with longitudinal live imaging showed that Disc1 supplementation increased ATP production in stressed neurons. Disc1 gene therapy promotes neuronal survival, reverses abnormal single-cell calcium dynamics, and restores visual responses. Our study demonstrates that enhancing anterograde mitochondrial transport is an effective strategy to alleviate metabolic stress and neurodegeneration.

Department of Neuroscience, University of Montreal, PO Box 6128, Station Centre-ville, Montreal, QC H3C 3J7, Canada; Neuroscience Division, Centre de recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), 900 Saint Denis Street, Montreal, QC H2X 0A9, Canada.

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