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.
