, 2008). Both exhibit robust and selective striatal and cortical atrophy with neurodegeneration primarily targeting the striatal medium PF-01367338 in vitro spiny neurons (MSNs) and a subset of cortical pyramidal neurons (Greenstein et al., 2007 and Rudnicki et al., 2008). Moreover, both HD and HDL2 brains contain intranuclear inclusions (NIs) that are ultrastructurally similar and are immunostained with ubiquitin and 1C2 (an antibody against the expanded polyQ epitope that can also recognize polyleucine; Trottier et al.,

1995 and Dorsman et al., 2002). The pattern of NI distribution in HD and HDL2 is similar, but not identical. They both have a higher density in the cortex and amygdala than in the striatum and NIs are rarely observed in the cerebellum or midbrain (Greenstein et al., 2007 and Rudnicki Regorafenib manufacturer et al., 2008). However, unlike those in HD, NIs in HDL2 are more frequent in the upper cortical layers II/III than deep cortical layers, and they are absent in the pons and medulla (Greenstein et al., 2007 and Rudnicki et al., 2008). Another key pathological difference between the two disorders is that NIs in HD, but not those

in HDL2, contain mutant huntingtin (mhtt) (Margolis et al., 2001). Therefore, the pathogenic origin of NIs in HDL2 remains to be uncovered. HDL2 is caused by a CTG/CAG expansion on chromosome 16q24.3 (Holmes et al., 2001). The expanded CTG/CAG repeats in HDL2 patients range from 40–59, with normal individuals carrying 6–28 nearly repeats. HD and HDL2 not only have comparable ranges of CTG/CAG repeat expansions, but also similar slopes in their inverse

relationships between the repeat length and age of onset for movement disorders (Margolis et al., 2004). The CTG repeat expansion is located within the variably spliced exon 2A of JPH3, which is not part of the main transcript encoding JPH3 protein ( Holmes et al., 2001). On the sense strand, three splice variants that include exon 2A have been described, placing the expanded CTG repeat in polyleucine or polyalanine open reading frames (ORFs) or in the 3′ untranslated region (UTR). Currently, the molecular pathogenic mechanisms for HDL2 remain an enigma (Margolis et al., 2005 and Orr and Zoghbi, 2007). Three possible mechanisms have been postulated. First, the expansion of the CUG repeat may reduce JPH3 mRNA expression leading to a partial loss of function for JPH3 protein, which normally tethers the plasma membrane to the endoplasmic reticulum to facilitate crosstalk between cell surface and intracellular ion channels ( Nishi et al., 2002 and Takeshima, 2001). In support of this theory, JPH3 knockout mice exhibit motor impairment but such mice do not appear to accumulate NIs or exhibit neurodegeneration ( Nishi et al., 2002).