Widespread expression of Huntington's disease gene (IT15) protein product

Abstract

Huntington's Disease (HD) is caused by expansion of a CAG repeat within a putative open reading frame of a recently identified gene, IT15. We have examined the expression of the gene's protein product using antibodies developed against the N-terminus and an internal epitope. Both antisera recognize a 350 kDa protein, the predicted size, indicating that the CAG repeat is translated into polyglutamine. The HD protein product is widely expressed, most highly in neurons in the brain. There is no enrichment in the striatum, the site of greatest pathology in HD. Within neurons, the protein is diminished in nuclei and mitochondria and is present in the soluble cytoplasmic compartment, as well as loosely associated with membranes or cytoskeleton, in cell bodies, dendrites, and axons. It is concentrated in nerve terminals, including terminals within the caudate and putamen. Thus, the normal HD gene product may be involved in common intracellular functions, and possibly in regulation of nerve terminal function. The product of the expanded allele is expressed, consistent with a gain of function mechanism for HD at the protein level.

Increased apoptosis, huntingtin inclusions and altered differentiation in muscle cell cultures from Huntington's disease subjects

“…1 In patients, progressive widespread brain atrophy, 2,3 leading to severe motor disability over time, is associated with early peripheral tissue dysfunction such as loss of body weight. 4,5 Hence, the pathological involvement of non-nervous tissues may contribute to the clinical features of HD.…”

Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease

“…14,15 The selectivity of neuronal death seen in HD striatum and cortex is remarkable given that huntingtin protein (Htt) is normally expressed throughout the central nervous system as well as in non-neuronal cells. [16][17][18] Htt is also widely distributed at the subcellular level and has been found within nuclei, perikarya, neurites, and synaptic elements. [16][17][18][19][20][21] Considering the widespread expression of Htt, it is interesting that the enkephalin and substance P-containing medium spiny neurons are vulnerable in the striatum, while large cholinergic and medium aspiny neurons are spared.…”

“…[16][17][18] Htt is also widely distributed at the subcellular level and has been found within nuclei, perikarya, neurites, and synaptic elements. [16][17][18][19][20][21] Considering the widespread expression of Htt, it is interesting that the enkephalin and substance P-containing medium spiny neurons are vulnerable in the striatum, while large cholinergic and medium aspiny neurons are spared. 14,[22][23][24] In the cortex, the pyramidal cortical projection neurons in layers III and V are vulnerable.…”

Mutant Huntingtin Impairs Post-Golgi Trafficking to Lysosomes by Delocalizing Optineurin/Rab8 Complex from the Golgi Apparatus

“…Htt is a huge protein with a widespread distribution in neurons, including cell bodies, dendrites and axons (Sharp et al, 1995). Detailed subcellular fractionation and microscopic studies have shown that htt is also associated with vesicles and microtubules (Difiglia et al, 1995;Hoffner et al, 2002), where it interacts with molecular motors that promote the transport of vesicles containing brain derived-neurotrophic factor (BDNF) (Gauthier et al, 2004).…”