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Heberto Quintero, Nicolas Belforte, Luis Alarcon-Martinez, Florence Dotigny, Sana El Hajji, Adriana Di Polo; Increased DISC1 expression restores mitochondrial axonal transport and rescues RGC function in glaucoma. Invest. Ophthalmol. Vis. Sci. 2021;62(8):1767.
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© ARVO (1962-2015); The Authors (2016-present)
Adequate distribution of mitochondria in retinal ganglion cells (RGCs) is crucial for energy balance and synaptic function. Here, we tested the hypotheses that: i) early deficits in mitochondrial transport in glaucoma contributes to RGC loss, ii) the adaptor protein Disrupted in Schizophrenia 1 (DISC1) is an essential regulator of mitochondrial trafficking along RGC axons, and iii) restoring mitochondrial transport is beneficial for RGCs survival and function.
Ocular hypertension was induced by intracameral injection of magnetic microbeads in Thy1-CFP-MitoS mice, a strain that allows mitochondria visualization in RGCs. Two-photon laser scanning microscopy (TPLSM) was used to image mitochondrial transport along RGC axons, followed by kymograph analysis. Levels of transport adaptor proteins were analyzed by qPCR using mRNA from FACS-sorted RGCs. DISC1 levels in RGCs were modulated using siRNA or recombinant adeno-associated virus serotype 2 (AAV2.DISC1). RGC function was assessed by measuring positive scotopic threshold responses (pSTR).
Live imaging using TPLSM revealed a selective reduction of anterograde mitochondrial transport along RGC axons soon after glaucoma induction (50% decrease vs. sham control, Student’s t-test p<0.001, n=35 axons/group, N=12-14 mice/group). Analysis of mitochondrial trafficking genes in RGCs showed reduced DISC1 transcript levels after glaucoma (Student’s t-test, p≤0.01, n=4/group). DISC1 protein, which is abundantly expressed by naïve RGCs, was also downregulated by ocular hypertension (Student’s t-test p≤0.05, n=6/group). siRNA-mediated silencing of DISC1 further reduced mitochondrial transport and exacerbated RGC death (14% reduction vs. control siRNA, ANOVA p<0.05, n=6/group). In contrast, AAV2.DISC1 fully restored mitochondrial mobility and promoted RGC survival in glaucomatous eyes (30% increase vs. control AAV, ANOVA p<0.001, n=6/group). AAV2.DISC1 also restored light-evoked pSTR amplitudes, indicative of RGC functional recovery.
Ocular hypertension triggers mitochondria axonal transport deficits and limits the availability of trafficking proteins, notably DISC1. Restoration of DISC1 levels is sufficient to rescue mitochondrial mobility, enhance RGC survival and light-evoked responses. These findings suggest that mitochondrial transport recovery is beneficial to improve RGC viability and function in glaucoma.
This is a 2021 ARVO Annual Meeting abstract.
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