Pleiotropic effects of mutant huntingtin on retinopathy in two mouse models of Huntington's disease
Huntington's disease (HD) is caused by the expansion of a CAG repeat, encoding a string of glutamines (polyQ) in the first exon of the huntingtin gene (HTTex1). This mutant huntingtin protein (mHTT) with extended polyQ forms aggregates in cortical and striatal neurons, causing cell damage and d...
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Elsevier
2025-02-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996124003826 |
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| author | Hui Xu Anakha Ajayan Ralf Langen Jeannie Chen |
| author_facet | Hui Xu Anakha Ajayan Ralf Langen Jeannie Chen |
| author_sort | Hui Xu |
| collection | DOAJ |
| description | Huntington's disease (HD) is caused by the expansion of a CAG repeat, encoding a string of glutamines (polyQ) in the first exon of the huntingtin gene (HTTex1). This mutant huntingtin protein (mHTT) with extended polyQ forms aggregates in cortical and striatal neurons, causing cell damage and death. The retina is part of the central nervous system (CNS), and visual deficits and structural abnormalities in the retina of HD patients have been observed. Defects in retinal structure and function are also present in the R6/2 and R6/1 HD transgenic mouse models that contain a gene fragment to express mHTTex1. We investigated whether these defects extend to the zQ175KI mouse model which is thought to be more representative of the human condition because it was engineered to contain the extended CAG repeat within the endogenous HTT locus. We found qualitatively similar phenotypes between R6/1 and zQ175KI retinae that include the presence of mHTT aggregates in retinal neurons, cone loss, downregulation of rod signaling proteins and abnormally elongated photoreceptor connecting cilia. In addition, we present novel findings that mHTT disrupts cell polarity in the photoreceptor cell layer and the retinal pigment epithelium (RPE). Furthermore, we show that the RPE cells from R6/1 mice contain mHTT nuclear inclusions, adding to the list of non-neuronal cells with mHTT aggregates and pathology. Thus, the eye may serve as a useful system to track disease progression and to test therapeutic intervention strategies for HD. |
| format | Article |
| id | doaj-art-24e11f79ac3e49a6ac4c46212c98d933 |
| institution | Kabale University |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-24e11f79ac3e49a6ac4c46212c98d9332025-01-24T04:44:38ZengElsevierNeurobiology of Disease1095-953X2025-02-01205106780Pleiotropic effects of mutant huntingtin on retinopathy in two mouse models of Huntington's diseaseHui Xu0Anakha Ajayan1Ralf Langen2Jeannie Chen3Department of Physiology & Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USADepartment of Physiology & Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USADepartment of Physiology & Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USACorresponding author at: Zilkha Neurogenetic Institute, ZNI 223, 1501 San Pablo St, Los Angeles, CA 90033, USA.; Department of Physiology & Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USAHuntington's disease (HD) is caused by the expansion of a CAG repeat, encoding a string of glutamines (polyQ) in the first exon of the huntingtin gene (HTTex1). This mutant huntingtin protein (mHTT) with extended polyQ forms aggregates in cortical and striatal neurons, causing cell damage and death. The retina is part of the central nervous system (CNS), and visual deficits and structural abnormalities in the retina of HD patients have been observed. Defects in retinal structure and function are also present in the R6/2 and R6/1 HD transgenic mouse models that contain a gene fragment to express mHTTex1. We investigated whether these defects extend to the zQ175KI mouse model which is thought to be more representative of the human condition because it was engineered to contain the extended CAG repeat within the endogenous HTT locus. We found qualitatively similar phenotypes between R6/1 and zQ175KI retinae that include the presence of mHTT aggregates in retinal neurons, cone loss, downregulation of rod signaling proteins and abnormally elongated photoreceptor connecting cilia. In addition, we present novel findings that mHTT disrupts cell polarity in the photoreceptor cell layer and the retinal pigment epithelium (RPE). Furthermore, we show that the RPE cells from R6/1 mice contain mHTT nuclear inclusions, adding to the list of non-neuronal cells with mHTT aggregates and pathology. Thus, the eye may serve as a useful system to track disease progression and to test therapeutic intervention strategies for HD.http://www.sciencedirect.com/science/article/pii/S0969996124003826Huntington diseaseCell polarityCiliopathyProtein aggregationRetinal degeneration |
| spellingShingle | Hui Xu Anakha Ajayan Ralf Langen Jeannie Chen Pleiotropic effects of mutant huntingtin on retinopathy in two mouse models of Huntington's disease Neurobiology of Disease Huntington disease Cell polarity Ciliopathy Protein aggregation Retinal degeneration |
| title | Pleiotropic effects of mutant huntingtin on retinopathy in two mouse models of Huntington's disease |
| title_full | Pleiotropic effects of mutant huntingtin on retinopathy in two mouse models of Huntington's disease |
| title_fullStr | Pleiotropic effects of mutant huntingtin on retinopathy in two mouse models of Huntington's disease |
| title_full_unstemmed | Pleiotropic effects of mutant huntingtin on retinopathy in two mouse models of Huntington's disease |
| title_short | Pleiotropic effects of mutant huntingtin on retinopathy in two mouse models of Huntington's disease |
| title_sort | pleiotropic effects of mutant huntingtin on retinopathy in two mouse models of huntington s disease |
| topic | Huntington disease Cell polarity Ciliopathy Protein aggregation Retinal degeneration |
| url | http://www.sciencedirect.com/science/article/pii/S0969996124003826 |
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