Xu Hui, Ajayan Anakha, Langen Ralf, Chen Jeannie
Department of Physiology & Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Department of Physiology & Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Neurobiol Dis. 2025 Feb;205:106780. doi: 10.1016/j.nbd.2024.106780. Epub 2024 Dec 28.
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.
亨廷顿舞蹈症（HD）由CAG重复序列扩增引起，该重复序列在亨廷顿基因（HTTex1）的第一个外显子中编码一串谷氨酰胺（polyQ）。这种具有延长polyQ的突变亨廷顿蛋白（mHTT）在皮质和纹状体神经元中形成聚集体，导致细胞损伤和死亡。视网膜是中枢神经系统（CNS）的一部分，并且已经观察到HD患者视网膜存在视觉缺陷和结构异常。在含有表达mHTTex1基因片段的R6/2和R6/1 HD转基因小鼠模型中也存在视网膜结构和功能缺陷。我们研究了这些缺陷是否延伸至zQ175KI小鼠模型，该模型被认为更能代表人类情况，因为它被设计为在内源性HTT基因座内包含延长的CAG重复序列。我们发现R6/1和zQ175KI视网膜之间存在定性相似的表型，包括视网膜神经元中存在mHTT聚集体、视锥细胞丧失、视杆信号蛋白下调以及光感受器连接纤毛异常伸长。此外，我们还提出了新的发现，即mHTT破坏了光感受器细胞层和视网膜色素上皮（RPE）中的细胞极性。此外，我们表明来自R6/1小鼠的RPE细胞含有mHTT核内包涵体，这增加了具有mHTT聚集体和病理学的非神经元细胞种类。因此，眼睛可能是追踪疾病进展和测试HD治疗干预策略的有用系统。
