Understanding the mechanisms that modulate the effects of mutant Huntingtin lowering in aging Huntington's disease model mice

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Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder that is caused by the expansion of a CAG triplet repeat encoding a stretch of polyglutamine (polyQ) within Huntingtin (HTT), the protein product of the HD gene. The HD mutation confers a deleterious gain-of-function, possibly via the expression of both toxic RNA transcripts and protein, together with potential loss of normal HTT function that affects a variety of cellular functions. A number of HTT lowering strategies are being developed–Phase III clinical trials testing the efficacy of anti-sense oligonucleotides (ASOs) targeting either total HTT expression or selectively mutant HTT (mHTT) expression are underway, while Htt lowering using other approaches (miRNA and splicing modulators) are currently in safety/tolerability trials or will begin such trials shortly. Many of the initial preclinical studies, however, did not examine the long-term effects of Htt lowering in aged models. Using a regulatable HD mouse model whose mHtt expression or total Htt expression are controlled via a Lac operator/repressor system, we found that global pre-symptomatic ~50% Htt lowering (starting prior to 3 months of age) of either mutant or total Htt expression was more beneficial in ameliorating HD mouse model phenotypes in comparison to later lowering (starting at 6 months of age or later), and that there were no obvious detrimental consequences from lowering total Htt expression in comparison to the allele-specific lowering of mHtt expression. However, we observed that in older mice, the beneficial effects of earlier Htt lowering were attenuated for some, but not all HD model phenotypes. We hypothesize that: (1) brain regions respond differentially to the amount and/or timing of mHtt lowering, and aging may exacerbate this effect, and (2) >50% reduction of mHtt expression may be needed to maintain homeostatic cellular and physiological functions whose efficiency declines with age. To test these hypotheses, and to provide a better understanding of how lowering mHtt expression affects homeostatic functions in older mice, we propose three aims. In (Aim 1), we will characterize the effects of globally lowering mHtt expression by ~75% using a different strain of Lac- regulatable HD mouse model to determine if the benefits of mHtt lowering can be extended beyond 12 months of age for all HD mouse model phenotypes. To determine if the DNA damage response and neuroimmflamation, two critical homeostatic functions that decline with age, can modulate the effect of mHtt lowering in older mice, we propose to characterize the DNA damage response in (Aim 2), while in (Aim 3), we propose to characterize activation of the inflammasome and measure meningeal lymphatic function in our mHtt-lowered mice and controls. Together, these aims should provide new insight into the degree of mHtt lowering that is needed to impact HD pathogenesis in aging mice. In addition, determining if two age-related pathways correlate with mHtt expression levels and/or HD model phenotypes could provide new potential therapeutic targets to be explored for the treatment of HD.