Abstract
Visual deficit is one of the complications of Huntington disease (HD), a fatal neurological disorder caused by CAG trinucleotide expansions in the Huntingtin gene, leading to the production of mutant Huntingtin (mHTT) protein. Transgenic HD R6/1 mice expressing human HTT exon1 with 115 CAG repeats recapitulate major features of the human pathology and exhibit a degeneration of the retina. Our aim was to gain insight into the ultrastructure of the pathological HD R6/1 retina by electron microscopy (EM). We show that the HD R6/1 retina is enriched with unusual organelles myelinosomes, produced by retinal neurons and glia. Myelinosomes are present in all nuclear and plexiform layers, in the synaptic terminals of photoreceptors, in the processes of retinal neurons and glial cells, and in the subretinal space. In vitro study shows that myelinosomes secreted by human retinal glial Müller MIO-M1 cells transfected with EGFP-mHTT-exon1 carry EGFP-mHTT-exon1 protein, as revealed by immuno-EM and Western-blotting. Myelinosomes loaded with mHTT-exon1 are incorporated by naive neuronal/neuroblastoma SH-SY5Y cells. This results in the emergence of mHTT-exon1 in recipient cells. This process is blocked by membrane fusion inhibitor MDL 28170. Conclusion: Incorporation of myelinosomes carrying mHTT-exon1 in recipient cells may contribute to HD spreading in the retina. Exploring ocular fluids for myelinosome presence could bring an additional biomarker for HD diagnostics.
Highlights
The retina is a part of the CNS, exhibiting similar principles of cellular organization and metabolism [1]
The retinal pigmented epithelium (RPE) layer in R6/1 retinal sections looked disorganized compared to the control (Figure 1a, bottom panel; Supplementary Materials Figure S1a)
We previously demonstrated in situ and in vitro that myelinosomes produced by Huntington disease (HD) R6/1 testis or by Sertoli cells transfected with EGFP-mutant Huntingtin (mHTT)-exon1, were loaded with mHTT-exon1 protein [43]
Summary
The retina is a part of the CNS, exhibiting similar principles of cellular organization and metabolism [1]. Several major neurodegenerative disorders such as Parkinson’s and Alzheimer’s disease or multiple sclerosis have manifestations in the eye. The epidemiology of HD reveals gross differences in the prevalence of HD by ancestry, with a much higher rate of the disease in populations of European descent, which varies between 1.6 and 12.3 cases per 100,000 [10]. In this context, there is an unmet need to identify preclinical biomarkers to select the high-risk population and predict the disease and its progression [11]
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