June 2020
Volume 61, Issue 7
ARVO Annual Meeting Abstract  |   June 2020
Characterizing the pathophysiology that underlies vision loss in the childhood neurodegenerative disease, Mucolipidosis type IV.
Author Affiliations & Notes
  • Marquis Walker
    Biology, James Madison University, Harrisonburg, Virginia, United States
  • Michael Pamonag
    Biology, James Madison University, Harrisonburg, Virginia, United States
  • Footnotes
    Commercial Relationships   Marquis Walker, None; Michael Pamonag, None
  • Footnotes
    Support  4VA grant
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 1280. doi:
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      Marquis Walker, Michael Pamonag; Characterizing the pathophysiology that underlies vision loss in the childhood neurodegenerative disease, Mucolipidosis type IV.. Invest. Ophthalmol. Vis. Sci. 2020;61(7):1280.

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

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Purpose : Retinal degenerative diseases (RDDs), including age-related macular degeneration, retinitis pigmentosa, and Leber congenital amaurosis are a broad group of disorders that affect 1 in every ~3000 people in the United States. In most RDDs regardless of the genetic origin, retinas show some disruption in rhodopsin trafficking, decreased photoresponse, and increased photoreceptor death. In this study we are using the Mucolipidosis type IV (MLIV) mouse model to understand the cause of photoreceptor cell death. MLIV is a lysosomal storage disorder which are the greatest cause of childhood onset neurodegeneration. MLIV results from loss of function mutations in the Mcoln1 gene that encodes the cation channel (Trpml1). Loss of Trpml1 function has been shown to disrupt cellular autophagy and phagocytic activity, which contributes to motor neuron cell death in MLIV. It is not clear why the light response of rod and cone photoreceptors in MLIV are sensitive to the loss Trpml1. We hypothesize that functional defects in photoreceptors of Mcoln1-/- mice is due to a disruption in trafficking of photoreceptor proteins across the connecting cilium of rod and cone cells.

Methods :

We use electroretinograms (ERGs) and protein analysis to measure age-dependent changes photoreceptor activity in the Mcoln1-/- mice. We also use immunohistochemistry to measure retinal protein expression and localization.

Results : Our results show a significant early decrease in light activation of Mcoln1-/- mice, and a 60% decrease in total rhodopsin in Mcoln1-/- retina. Analysis of total retinal proteins in Mcoln1-/- retina also show a significant loss of a protein required for ciliogenesis, Bardet-Biedl syndrome 4 (BBS4). Mcoln1-/- mice photoreceptors show morphological defects at the connecting cilium and shorter outer segment that are consistent with the loss of BBS4 expression. Accumulation of vesicles in the inner segment also suggests a disruption of trafficking to the outer segment.

Conclusions : Currently, there are no known cures for MLIV or the retinal degeneration seen in many lysosomal storage disorders. However, restorative therapies are thought to be a promising pathway for treatment of retinal degenerative disorders. We are identifying the functional pathways that are disrupted in photoreceptors to identify targets for treatment and restoring photoreceptive activity.

This is a 2020 ARVO Annual Meeting abstract.


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