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ORIGINAL RESEARCH article
Front. Aging Neurosci.
Sec. Parkinson’s Disease and Aging-related Movement Disorders
Volume 16 - 2024 |
doi: 10.3389/fnagi.2024.1434551
This article is part of the Research Topic From Genetic Discovery to Clinical Practice: Bridging the Gap in Huntington's Disease View all articles
Abnormal outer and inner retina in a mouse model of Huntington's disease with age
Provisionally accepted- Jinan University, Guangzhou, Guangdong Province, China
Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by motor dysfunction and cognitive decline. While retinal abnormalities have been documented in some HD patients and animal models, the nature of these abnormalities-specifically whether they originate in the inner or outer retina-remains unclear, particularly regarding their progression with age. This study investigates the retinal structure and function in HD transgenic mice (R6/1) compared to C57BL/6J control mice at 2, 4, and 6 months of age, encompassing both pre-symptomatic and symptomatic stages of HD. Pathological assessments of the striatum and evaluations of motor function confirmed significant HD-related alterations in R6/1 mice at 6 months. Visual function was subsequently analyzed, accompanied by immunofluorescent staining of retinal and optic nerve tissues over time. Our findings revealed that R6/1 mice exhibited pronounced HD symptoms at 6 months, characterized by neuronal loss in the striatum and impaired locomotor abilities. Functionally, visual acuity declined at 6 months, while retinal light responses began to deteriorate by 4 months. Structurally, R6/1 mice demonstrated a global reduction in cone opsin expression as early as 2 months, with a decrease in rhodopsin levels at 4 months, alongside a thinner retinal structure compared to controls. Notably, rod bipolar cell populations were diminished at 6 months, exhibiting shorter dendritic branches and reduced synaptic connections with photoreceptors in the outer retina.Additionally, ganglion cell numbers in the inner retina decreased at 6 months, accompanied by aberrant neural fibers in the optic nerve. Microglial activation was evident at 4 months, while astrocytic activation was observed at 6 months. Aggregates of mutant huntingtin (mHTT) were first detected in the ganglion cell layer and optic nerve at 2 months, subsequently disseminating throughout all retinal layers with advancing age. These results indicate that retinal pathology in R6/1 mice manifests earlier in the outer retina than in the inner retina, which does not align with the progression of mHTT aggregation. Consequently, the R6/1 mouse retina may serve as a more effective model for elucidating the mechanisms underlying HD and evaluating potential therapeutic strategies, rather than functioning as an early diagnostic tool for the disease.
Keywords: Huntington's disease, R6/1, Mutant huntingtin, Retina, photoreceptor, ganglion cell, Bipolar cell, Optic Nerve
Received: 20 May 2024; Accepted: 11 Oct 2024.
Copyright: © 2024 Yang, Huang, Guo, Li, Wu, Zhang, Yan and Xu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Xuemeng Guo, Jinan University, Guangzhou, 510632, Guangdong Province, China
Yintian Li, Jinan University, Guangzhou, 510632, Guangdong Province, China
Jiaxi Wu, Jinan University, Guangzhou, 510632, Guangdong Province, China
Zaijun Zhang, Jinan University, Guangzhou, 510632, Guangdong Province, China
Sen Yan, Jinan University, Guangzhou, 510632, Guangdong Province, China
Ying Xu, Jinan University, Guangzhou, 510632, Guangdong Province, China
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