Abstract
Huntington’s disease (HD) is an inherited neurodegenerative disorder that primarily affects the medium-size GABAergic neurons of striatum. The R6/2 mouse line is one of the most widely used animal models of HD. Previously the hallmarks of HD-related pathology have been detected in photoreceptors and interneurons of R6/2 mouse retina. Here we aimed to explore the survival of retinal ganglion cells (RGCs) and functional integrity of distinct retinal cell populations in R6/2 mice. The pattern electroretinography (PERG) signal was lost at the age of 8 weeks in R6/2 mice in contrast to the situation in wild-type (WT) littermates. This defect may be attributable to a major reduction in photopic ERG responses in R6/2 mice which was more evident in b- than a-wave amplitudes. At the age of 4 weeks R6/2 mice had predominantly the soluble form of mutant huntingtin protein (mHtt) in the RGC layer cells, whereas the aggregated form of mHtt was found in the majority of those cells from the 12-week-old R6/2 mice and onwards. Retinal astrocytes did not contain mHtt deposits. The total numbers of RGC layer cells, retinal astrocytes as well as optic nerve axons did not differ between 18-week-old R6/2 mice and their WT controls. Our data indicate that mHtt deposition does not cause RGC degeneration or retinal astrocyte loss in R6/2 mice even at a late stage of HD-related pathology. However, due to functional deficits in the rod- and cone-pathways, the R6/2 mice suffer progressive deficits in visual capabilities starting as early as 4 weeks; at 8 weeks there is severe impairment. This should be taken into account in any behavioral testing conducted in R6/2 mice.
Highlights
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder which is caused by a CAG repeat expansion in the Huntingtin gene on chromosome 4 [1,2]
Between 8–12 weeks of age, the photopic ERG continued to deteriorate (Fig. 2, left column), which led to a significant increase in the b-wave latency at 12-week group compared to WT mice (z522.7, p,0.05)
Photopic ERG a- and b-wave latencies had a tendency to increase in R6/2 mice, whereas amplitudes did not change with age ( Fig. 2, left column)
Summary
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder which is caused by a CAG repeat expansion in the Huntingtin gene on chromosome 4 [1,2]. In normal individuals the number of CAG repeats varies between 16 and 20, whereas HD-affected individuals have a tract of 36 CAG repeats and more [3]. An expanded polyglutamine tract leads to the production of mutant form of huntingtin protein (mHtt). The exact mechanism of mHtt aggregation is still unknown, but a number of evidence suggests the existence of several mechanisms employing abnormally expanded repeats of glutamine (for a review see [4]). MHtt can co-exist in the cell as monomer, oligomer and large cytoplasmic and nuclear inclusions [5,6,7]. Small oligomers of mHtt were proposed to be the most toxic form of mHtt [8]
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