Why this strain is free from the early onset behavioral symptoms one would expect in what is essentially an N-terminal transgene HD model is still under investigation. Knockin mouse P450 inhibitor neuropathology, as with their symptoms, usually occurs very late in life and is minor in comparison to transgenic strains. HdhQ72-80 mice demonstrate loss of brain weight by 16 months (Shelbourne et al., 1999), while NIIs are primarily seen in striatal MSNs. Knockins with 94 repeats demonstrate striatal NIIs by 18 months (Menalled et al., 2002), while HdhQ111 mice show NII appearance at

an earlier age (10 months), and mHtt nuclear accumulation is evident at a very early (6 weeks) age (Wheeler et al., 2000). HdhQ150 knockins lose as much as 40% of striatal volume and neurons by 23 months, but significant gliosis and NIIs appear by 10–14 months (Heng et al., 2007, Lin et al., 2001, Tallaksen-Greene et al., 2005 and Yu et al., 2003). Degenerating neurons are not apoptotic in this strain, though occasional

dark neurons are encountered. Knockin mice with 140 CAG repeats display relatively early onset striatal www.selleckchem.com/products/pd-0332991-palbociclib-isethionate.html NIIs and neuropil aggregates (4 months) becoming progressively stronger in other brain regions as well by 6 months (Menalled et al., 2003). These data do not imply that knockin brains only present with abnormality in old age, as HdhQ111 embryos demonstrate impaired neurogenesis as early as embryonic day 13.5 (Molero et al., 2009). Protein context clearly influences neuropathology and symptoms in HD, as other polyglutamine disorders such as SBMA, DRPLA, and the various

spinocerebellar ataxias (reviewed in Yamada et al., 2008) produce distinct vulnerable neuronal populations and motor symptoms. Posttranslational modifications influence progression, as ablation of caspase-6 cleavage sites within the YAC transgene yields a mouse that demonstrates no behavioral symptoms or striatal atrophy along with a delay in mHTT translocation to the nucleus (Graham et al., 2006). Also, while only 17 residues lie N-terminal to the polyQ repeat in human HTT, these Oxygenase play a role in neuropathology; phosphomimetic mutations of serines 13 and 16 prevent aggregation and symptom onset in parallel BACHD lines (Gu et al., 2009). While inclusions are a historic histological hallmark of HD, evidence continues to mount that their presence does not correlate with toxicity, as seen in chimaeric R6/2 or in Ss mice. The theory that inclusions represent a sequestration site for mHTT, while smaller oligomers mediate toxicity, is consistent with neuropathological data in mice but is hard to prove with causative data. It represents an intriguing therapeutic option though, that perhaps altering aggregation kinetics by accelerating macroaggregation or reducing oligomerization would slow toxicity.