Abstract
Huntington's disease (HD) is an autosomal dominant, progressive and fatal neurological disorder caused by an expansion of CAG repeats in exon-1 of the huntingtin gene. The encoded poly-glutamine stretch renders mutant huntingtin prone to aggregation. HdhQ150 mice genocopy a pathogenic repeat (∼150 CAGs) in the endogenous mouse huntingtin gene and model predominantly pre-manifest HD. Treating early is likely important to prevent or delay HD, and HdhQ150 mice may be useful to assess therapeutic strategies targeting pre-manifest HD. This requires appropriate markers and here we demonstrate, that pre-symptomatic HdhQ150 mice show several dramatic mutant huntingtin gene-dose dependent pathological changes including: (i) an increase of neuronal intra-nuclear inclusions (NIIs) in brain, (ii) an increase of extra-nuclear aggregates in dentate gyrus, (iii) a decrease of DARPP32 protein and (iv) an increase in glial markers of neuroinflammation, which curiously did not correlate with local neuronal mutant huntingtin inclusion-burden. HdhQ150 mice developed NIIs also in all retinal neuron cell-types, demonstrating that retinal NIIs are not specific to human exon-1 R6 HD mouse models. Taken together, the striking and robust mutant huntingtin gene-dose related changes in aggregate-load, DARPP32 levels and glial activation markers should greatly facilitate future testing of therapeutic strategies in the HdhQ150 HD mouse model.
Highlights
Huntington’s disease (HD) is a progressive fatal neurodegenerative disease caused by CAG repeat expansions in the huntingtin (HTT) gene
To compare nuclear inclusions (NIIs) and extra-nuclear aggregate-load in HdhQ150 HOM and HET mouse brains, mHtt deposits were detected with MW8, an antibody that recognizes a distinct epitope in mHtt aggregates [35]
Previous immunohistochemical analyses have shown that the number and size of MW8+ NIIs in the HdhQ150 HET mouse brain gradually increased with age and most prominently in the striatum [17]
Summary
Huntington’s disease (HD) is a progressive fatal neurodegenerative disease caused by CAG repeat expansions in the huntingtin (HTT) gene. The repeat encodes a stretch of glutamines (polyQ) near the N-terminus of huntingtin (HTT). The polyQ renders these fragments prone to form soluble aggregates, large insoluble extra-nuclear aggregates and neuronal intra-nuclear inclusions (NIIs). These neuropathological hallmarks of HD [5,6,7] were thought to cause neuronal toxicity [8] but evidence has mounted, that aggregate formation may provide neuroprotection by neutralizing toxic soluble mutant huntingtin fragments [9,10,11]
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