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Mary A Johnson, Harald Gelderblom, Klaus Rüther, Josef Priller, Steven L Bernstein; Evidence that Huntington’s Disease Affects Retinal Structure and Function. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1644.
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© ARVO (1962-2015); The Authors (2016-present)
Huntington’s disease (HD) is a fatal autosomal dominant genetic disease, characterized by progressive neurologic degeneration affecting muscle coordination, cognition and mood/psychiatric health. HD is caused by a trinucleotide expansion repeat mutation in the Huntingtin (HTT) gene. Disease symptoms typically appear between the 2nd and 4th decades of life, based on the extent of the expansion-mutation. Numerous areas in the affected brain contain HTT-inclusion bodies and protein aggregates produced by the mutant HTT protein. While HTT expansion repeat transgenics have been shown to exhibit retinal photoreceptor degeneration, these models were hampered by artificially long expansions that may cause ‘off effects’. We wanted to evaluate retinal function and structure in an HTT model that more closely resembles the human disease.
Transgenic knock-in Huntington’s rats containing the human HTT gene with a 60-75 expansion repeat were used. Both Wild type (WT) and mutant pairs from the same litters were evaluated, and at different ages. Following at least 12 hours of dark-adaptation, we measured electroretinograms (ERGs) in pairs of HTT rats and their WT littermates, using the ISCEV protocol and an additional paradigm we developed to expose changes in presumed horizontal cell function. This test measured disinhibition of the photopic response when recorded on a dim vs. bright background. Rats were euthanized shortly thereafter and retinas immunostained for HTT, calbindin (stains horizontal cells), Choline acetyl transferase (ChAT) (stains a subset of amacrine cells), and evaluated by confocal microscopy.
No differences were seen in the ERG a- and b-waves of the HTT and normal rats. However, HTT rats showed reduced oscillatory potential amplitudes and disinhibition of the photopic response. Immunohistochemistry showed HTT accumulation in the horizontal cells and suggested a loss of ChAT (+)-amacrine cells.
Huntington’s disease appears to selectively affect retinal interneurons, causing an unusual inner retinal degeneration, the first such described. Since the disinhibition test appears to selectively target horizontal cell function, this test may be a potential biomarker for future treatment studies.
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