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

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 de-livery was sufficient to rescue anterograde transport and replenish axonal mitochondria. A genetically en-coded 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 sin-gle-cell calcium dynamics, and restores visual responses. Our study demonstrates that enhancing antero-grade mitochondrial transport is an effective strategy to alleviate metabolic stress and neurodegeneration.

Automated summary

Deficits in mitochondrial transport are a common feature of neurodegenerative diseases. Ocular hypertension disrupts mitochondrial anterograde axonal transport and leads to energy decline in vulnerable neurons. Disc1 gene therapy can enhance anterograde mitochondrial transport, promote neuronal survival, and restore normal neural activity.