Huntington disease (HD) is a progressive neurodegenerative disorder characterized by emotional, cognitive, and motor dysfunctions. Aggregation of huntingtin is a hallmark of HD and, therefore, a crucial parameter for the evaluation of HD animal models. We investigated here the regional, cellular, and subcellular distribution of N-terminal huntingtin aggregates and associated neuropathological changes in the forebrain of a rat transgenic for HD (tgHD). The tgHD rat brain showed enormously enlarged lateral ventricles and a similar atrophy of cortical and subcortical areas as known in HD patients. Huntingtin aggregates of varying size and forms were regionally identified in neuronal nuclei, cytoplasm, dendrites, dendritic spines, axons, and synaptic terminals, closely resembling the results described earlier for human HD brains and in established HD mouse models. Huntingtin aggregates in mitochondria support mitochondrial dysfunction as contributing to the disease pathogenesis. Dark cell degeneration was reminiscent of results in HD individuals and HD mouse models. Interestingly, huntingtin aggregates were especially well accumulated in two interacting limbic forebrain systems, the ventral striatopallidum and the extended amygdala, which may contribute to the early onset of emotional changes observed in the tgHD rat. In conclusion, the tgHD rat model reflects to a remarkable extent the cellular and subcellular neuropathological key features as observed in human HD and HD mouse brains and hints of changes in limbic forebrain systems, which may elucidate the emotional dysfunction in the tgHD rat and affective disturbances in HD patients.

Recent studies indicate that the visual system appears more frequently affected in polyglutamine diseases than expected previously. Here, we investigated retinal degenerations in adult transgenic R6/2 mice, a model for Huntington's disease (HD). Light microscopical analysis revealed retinal dystrophy all over the retina, with central areas showing major effects. Electron microscopical analysis showed strong degenerations of outer and inner photoreceptor segments, shrinkage of photoreceptor cell somata, and signs of degeneration in photoreceptor terminals in the outer plexiform layer. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling showed hints of apoptosis. Mutant huntingtin and ubiquitin were expressed in all classes of retinal neurons, the pigment epithelium, and to a minor extent in neuropil structures. For investigating possible links to functional impairments in the rod-cone pathway, expression levels of three connexins (Cx) were compared in R6/2 and wildtype mice retinae. In R6/2 mice, expression of Cx36, the major neuronal connexin in the retina, was slightly reduced in the outer plexiform layer, indicating affected photoreceptor terminals as detected at the electron microscopical level. In contrast, Cx45, a putative neuronal connexin in the retina, was remarkably reduced in the inner plexiform layer of R6/2 mice. This result corresponded to fainter signals of Cx45 mRNA as documented by in situ hybridization and to a lower level of mCx45 cDNA as obtained by polymerase chain reaction after reverse transcription, suggesting functional deficits in spatial processing of Cx45-mediated gap junction coupling due to transgene-induced retinal degenerations. Thus, it is important to clarify the meaning of visual involvement in HD.

No abstract

No abstract

No abstract

No abstract

Neuropathology of Huntington’s disease (HD) presents with progredient neuronal cell loss mainly in the striatum, but also in multiple other brain areas suggesting HD as a multisystem neurodegenerative disorder. Mutant huntingtin aggregates are the characteristic hallmark of HD. The aggregates are misfolded proteins varying in location, form, size and structural composition indicating a complex involvement in neurotoxicity. The question if and how the aggregates and many interacting protein partners may lead to cell death is continuously a matter of debate. The role of mutant huntingtin is more than ever of paramount importance as present genetic therapeutic approaches try to target downregulation of the Huntingtin gene expression and/or lowering the corresponding protein. In this context—and these aspects are focussed—it is of crucial interest to elucidate the regional distribution as well as the cellular and subcellular localization of aggregates in established animal models of HD and in affected HD brains.