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Mouse Eye Enucleation for Remote High-throughput Phenotyping
Published on: November 19, 2011
Pleiotropic effects of mutant huntingtin on retinopathy in two mouse models of Huntington's disease
Hui Xu1, Anakha Ajayan1, Ralf Langen1
1Department of Physiology & Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Insights
Huntington's disease (HD) pathology affects the retina, causing cell damage and visual deficits. The zQ175KI mouse model shows similar retinal defects to other models, indicating the eye
Area of Science:
- Neuroscience
- Genetics
- Ophthalmology
Background:
- Huntington's disease (HD) is a neurodegenerative disorder caused by CAG repeat expansion in the huntingtin gene.
- Mutant huntingtin protein (mHTT) forms aggregates, leading to neuronal damage and cell death.
- Retinal abnormalities and visual deficits are observed in HD patients and mouse models.
Purpose of the Study:
- To investigate retinal pathology in the zQ175KI mouse model of Huntington's disease.
- To compare retinal phenotypes between zQ175KI and R6/1 mouse models.
- To explore the potential of the retina as a biomarker for HD progression and therapeutic testing.
Main Methods:
- Histological analysis of retinal tissues from zQ175KI and R6/1 mice.
- Immunohistochemistry to detect mHTT aggregates and signaling proteins.
- Assessment of photoreceptor structure and cell polarity.
Main Results:
- Similar retinal phenotypes were observed in zQ175KI and R6/1 mice, including mHTT aggregates, cone loss, and altered rod signaling.
- Abnormally elongated photoreceptor connecting cilia and disrupted cell polarity in photoreceptor and retinal pigment epithelium (RPE) cells were identified.
- mHTT nuclear inclusions were found in RPE cells of R6/1 mice.
Conclusions:
- The zQ175KI mouse model exhibits retinal pathology relevant to Huntington's disease.
- The eye displays mHTT-induced cellular disruptions, including polarity defects and non-neuronal inclusions.
- The retina offers a potential avenue for monitoring HD progression and evaluating treatments.
Abstract:
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.
