Vignesh Subramanian ’24

Huntington’s disease (HD) is a genetic neurodegenerative disorder that causes progressive development of involuntary movements and decline of memory and cognitive abilities. The disease is characterized by the aggregation of abnormally long huntingtin protein (mHtt), a product of mutations in the HTT gene that cause excessive ‘CAG’ nucleotide sequence repeats within the protein’s coding DNA sequence. Such mHtt aggregation triggers cell death processes among the projection neurons of the striatum, the subcortical part of the forebrain responsible for receiving signaling inputs necessary for voluntary movement. This neuronal loss can be observed with examination of animal retinas, which along with optic nerves are considered extensions of the brain that are part of the central nervous system (CNS); as such, ocular imaging of retinal anatomy can provide key insights into disrupted maturation in the neocortex. However, previous studies could not conclude definitively that HD pathology actually manifests in human or mouse retinas. To establish this for certain, a study conducted by the University of Eastern Finland explored an approach by which HD could be detected in animal retinas with non-invasive eye examination techniques. 

Researchers first obtained transgenic mice of the R6/2 line, the most extensively utilized model of HD bred to carry a region of a mutant human HTT gene, and compared the survival of retinal ganglion cells (RGCs) in their eyes to that in wild type mice. All subjects were submitted to electroretinography (ERG) and visual evoked potential (VEP) procedures, which exposed them to varying amounts of light that induced electrical responses captured by electrodes; the measured voltages of these responses were then used to assess retinal and cortical function, respectively. The two particular stimuli used – flash and pattern electroretinography, or FERG and PERG – highlighted responsive electrical activity in rod-and-cone systems and RGCs. Following histological and statistical analyses of this data, researchers found that mHtt aggregation did not significantly contribute to RGC breakdown or retinal astrocyte loss. However, the R6/2 mice demonstrated shifts in electrical activity between their day and night vision with cone-driven PERG signals disappearing entirely by 8 weeks of age, directly tying compromised rod-and-cone systems to deficits in visual responses. Overall, this study demonstrated that HD manifestation can in fact be observed in the retinas of the disease’s most commonly used lab model, which may in turn augment painless diagnoses of HD in human beings using visual electrophysiology tests.

Works Cited:

[1] S. Ragauskas, et al., Early Retinal Function Deficit without Prominent Morphological Changes in the R6/2 Mouse Model of Huntington’s Disease. Public Library of Science (2019). doi: 10.1371/journal.pone.0113317.

[2] Image retrieved from: https://www.drugtargetreview.com/news/14455/brain-diseases-manifest-retina-eye/