June 2020
Volume 61, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2020
Increased expression of DISC1 restores mitochondrial axonal transport and promotes RGC survival in glaucoma: a live imaging study
Author Affiliations & Notes
  • Heberto Q Quintero
    Neuroscience, University of Montreal Hospital Research Center, Montreal, Quebec, Canada
  • Nicolas Belforte
    Neuroscience, University of Montreal Hospital Research Center, Montreal, Quebec, Canada
  • Luis Alarcon-Martinez
    Neuroscience, University of Montreal Hospital Research Center, Montreal, Quebec, Canada
  • Sana EL HAJJI
    Neuroscience, University of Montreal Hospital Research Center, Montreal, Quebec, Canada
  • Adriana Di Polo
    Neuroscience, University of Montreal Hospital Research Center, Montreal, Quebec, Canada
  • Footnotes
    Commercial Relationships   Heberto Quintero, None; Nicolas Belforte, None; Luis Alarcon-Martinez, None; Sana EL HAJJI, None; Adriana Di Polo, None
  • Footnotes
    Support  Canadian Institutes of Health Research (CIHR)
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 1162. doi:
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      Heberto Q Quintero, Nicolas Belforte, Luis Alarcon-Martinez, Sana EL HAJJI, Adriana Di Polo; Increased expression of DISC1 restores mitochondrial axonal transport and promotes RGC survival in glaucoma: a live imaging study. Invest. Ophthalmol. Vis. Sci. 2020;61(7):1162.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Disruption of anterograde axonal transport is an early pathological feature of glaucomatous injury. Adequate distribution of mitochondria in retinal ganglion cell (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, and ii) the adaptor protein Disrupted in Schizophrenia 1 (DISC1) is an essential regulator of mitochondrial trafficking along RGC axons.

Methods : 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 live mitochondrial transport along RGC axons followed by kymograph analysis. mRNA levels of mitochondrial adaptor proteins were analyzed in FACS-sorted RGCs. DISC1 levels in RGCs were modulated using short-interference siRNA or recombinant adeno-associated virus (AAV).

Results : Our real-time TPLSM data show substantial reduction of anterograde mitochondrial transport along RGC axons soon after glaucoma induction relative to sham-injected controls (50% decrease, Student’s t-test p<0.001, N= 12-14 mice/group, n=35 axons/group). Analysis of trafficking gene transcript levels showed marked DISC1 reduction after glaucoma induction (Student’s t-test, p≤0.01, N=4/group). DISC1 protein, which is abundantly expressed by naïve (non-injured) RGCs, was also downregulated by ocular hypertension (Student’s t-test p≤0.05, N=6 mice/group). siRNA-mediated attenuation of DISC1 further reduced mitochondrial transport and exacerbated RGC death (14% reduction vs. control siRNA, ANOVA p<0.05, n=6 mice/group). In contrast, AAV-driven DISC1 expression fully restored mitochondrial mobility and promoted RGC survival in glaucomatous eyes (30% increase vs. control AAV, ANOVA p<0.001, n=6/group).

Conclusions : Our data support these conclusions: i) ocular hypertension triggers early mitochondrial transport deficits and limits the availability of trafficking proteins, notably DISC1, ii) DISC1 supplementation is sufficient to restore mitochondrial mobility and enhance RGC survival. These findings suggest that mitochondrial transport rescue is beneficial to improve RGC function and viability in glaucoma.

This is a 2020 ARVO Annual Meeting abstract.

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