Striatal oligodendrogliogenesis and neuroblast recruitment are increased in the R6/2 mouse model of Huntington's disease.

The subventricular zone (SVZ) is one of the two major neurogenic regions in the adult mammalian brain. Its close proximity to the striatum suggests that a cell-based therapeutic strategy for the treatment of Huntington's disease (HD) is possible. To achieve this, it is important to understand how adult cell production, migration and differentiation may be altered in the HD brain. In this study, we quantified the number of adult-born striatal cells and characterized their fate in the R6/2 transgenic mouse model of HD. We found that the number of new striatal cells was approximately two-fold greater in R6/2 vs. wild type mice, while SVZ cell proliferation was not affected. Using cell-type specific markers, we demonstrated that the majority of new striatal cells were mature oligodendrocytes or oligodendroglial precursors that were intrinsic to the striatum. We also detected a significant increase in the number of migrating neuroblasts that appeared to be recruited from the SVZ to the striatum. However, these neuroblasts did not mature into neurons and most were lost between 1 and 2 weeks of cell age. Crossing the R6/2 mice with mice the over-expressing brain-derived neurotrophic factor in the striatum increased the numbers of neuroblasts that survived to 2 weeks, but did not promote their differentiation. Together, our data indicate that the potential treatment of HD based on manipulating endogenous progenitor cells should take into consideration the apparent enhancement in striatal oligodendrogliogenesis and the limited ability of recruited SVZ neuroblasts to survive long-term and differentiate in the diseased striatum.

Palmitoylation and trafficking of GAD65 are impaired in a cellular model of Huntington's disease.

HD (Huntington's disease) is caused by an expanded polyQ (polyglutamine) repeat in the htt (huntingtin protein). GABAergic medium spiny neurons in the striatum are mostly affected in HD. However, mhtt (mutant huntingtin)-induced molecular changes in these neurons remain largely unknown. The present study focuses on the effect of mhtt on the subcellular localization of GAD (glutamic acid decarboxylase), the enzyme responsible for synthesizing GABA (γ-aminobutyric acid). We report that the subcellular distribution of GAD is significantly altered in two neuronal cell lines that express either the N-terminus of mhtt or full-length mhtt. GAD65 is predominantly associated with the Golgi membrane in cells expressing normal htt; however, it diffuses in the cytosol of cells expressing mhtt. As a result, vesicle-associated GAD65 trafficking is impaired. Since palmitoylation of GAD65 is required for GAD65 trafficking, we then demonstrate that palmitoylation of GAD65 is reduced in the HD model. Furthermore, overexpression of HIP14 (huntingtin-interacting protein 14), the enzyme responsible for palmitoylating GAD65 in vivo, could rescue GAD65 palmitoylation and vesicle-associated GAD65 trafficking. Taken together, our data support the idea that GAD65 palmitoylation is important for the delivery of GAD65 to inhibitory synapses and suggest that impairment of GAD65 palmitoylation by mhtt may lead to altered inhibitory neurotransmission in HD.