Disease relevance of HD

• The HAP-1 protein is enriched in the brain, suggesting a possible basis for the selective brain pathology of HD [1].
• Huntington's disease (HD) is an inherited neurodegenerative disorder [2].
• Our data suggest that CIP4 accumulation and cellular toxicity may have a role in HD pathogenesis [3].
• Using two mouse models of HD, we demonstrate that the urea cycle deficiency characterized by hyperammonemia, high blood citrulline and suppression of urea cycle enzymes is a prominent feature of HD [4].
• The possible relationship of HAP1 and nNOS in the brain is reminiscent of the relationship of dystrophin and nNOS in skeletal muscle and suggests a role of NO in Huntington disease, analogous to its postulated role in Duchenne muscular dystrophy [5].

Psychiatry related information on HD

• Expanded polyglutamine repeats have been proposed to cause neuronal degeneration in Huntington's disease (HD) and related disorders, through abnormal interactions with other proteins containing short polyglutamine tracts such as the transcriptional coactivator CREB binding protein, CBP [6].
• Dementia may be a feature of other neurodegenerative diseases such as HD, dentatorubro-pallidoluysian atrophy (DRPLA), diseases caused by mutations of the prion protein gene (PRNP), spinocerebellar ataxias (SCA), and familial parkinsonism [7].
• OBJECTIVE: To examine the cognitive manifestations of Huntington disease (HD) with respect to age, clinical onset, progression, and genetic analyses [8].
• Sumoylation has been linked to the pathogenesis of a variety of disorders including Alzheimer's disease (AD), Huntington's disease (HD), and type 1 diabetes (T1D) [9].
• The characteristic symptoms of HD are involuntary choreiform movements, cognitive impairment, mood disorders, and behavioral changes which are chronic and progressive over the course of the illness [10].
• We discuss the role of normal huntingtin in transcriptional regulation and misregulation in Huntington's disease in relation to potentially analogous model systems, and to other polyglutamine disease proteins [11].

High impact information on HD

• Transcriptional deregulation and altered energy metabolism have been implicated in HD pathogenesis [12].
• Crossbreeding of PGC-1alpha knockout (KO) mice with HD knockin (KI) mice leads to increased neurodegeneration of striatal neurons and motor abnormalities in the HD mice [12].
• Huntington's disease (HD) is an inherited neurodegenerative disease caused by a glutamine repeat expansion in huntingtin protein [12].
• We report here that mutant huntingtin causes disruption of mitochondrial function by inhibiting expression of PGC-1alpha, a transcriptional coactivator that regulates several metabolic processes, including mitochondrial biogenesis and respiration [12].
• Huntington disease is a fatal neurodegenerative disorder caused by expansion of a polyglutamine tract in the protein huntingtin (Htt), which leads to its aggregation in nuclear and cytoplasmic inclusion bodies [13].

Chemical compound and disease context of HD

• The resultant ammonia toxicity might exacerbate the neurological deficits of HD [4].
• Huntington's disease (HD) occurs when the widely expressed protein huntingtin contains an expanded glutamine repeat [14].
• In the search for neuroprotective factors in Huntington's disease, we found that insulin growth factor 1 via activation of the serine/threonine kinase Akt/PKB is able to inhibit neuronal death specifically induced by mutant huntingtin containing an expanded polyglutamine stretch [15].
• Indeed, upon IGF-1 activation, Akt phosphorylates polyQ-huntingtin at serine 421 and abrogates its toxicity [16].
• Hyperhomocysteinaemia in treated patients with Huntington's disease homocysteine in HD [17].

Biological context of HD

• Our results show that huntingtin is cleaved by cysteine proteases and suggest that HD might be a disorder of inappropriate apoptosis [18].
• Pathogenesis in HD seems to involve the formation of neuronal intranuclear inclusions and the abnormal regulation of transcription and signal transduction [3].
• Using spectrophotometric assays in postmortem brain tissue, we found evidence of impaired oxidative phosphorylation enzyme activities restricted to the basal ganglia in HD brain, while enzyme activities were unaltered in three regions relatively spared by HD pathology (frontal cortex, parietal cortex, and cerebellum) [19].
• A key strategy for understanding HD pathology is to identify signaling cascades initiated by mutant Htt that lead to neuronal cell death and dysfunction [20].
• These findings reveal a singular, new subcellular phenotype in HD cells [21].

Anatomical context of HD

• Citrate synthase-corrected complex II-III activity was markedly reduced in both HD caudate (-29%) and putamen (-67%), and complex IV activity was reduced in HD putamen (-62%) [19].
• Both the mitochondria and the nucleus play an important role in HD pathology [20].
• Huntington's disease (HD) is a devastating central nervous system disorder [22].
• Finally, the total yield of fibroblasts per culture flask (as judged by protein content) was significantly greater for the stressed HD fibroblasts than for the escapee and control fibroblasts at 2 and 3 weeks after withholding medium [23].
• Here we report that the neurospecific phosphoprotein PACSIN 1, which has been implicated as playing a central role in synaptic vesicle recycling, interacts with huntingtin via its C-terminal SH3 domain [24].

Associations of HD with chemical compounds

• Treatments aimed at repairing the urea cycle deficiency may provide a new strategy for dealing with HD [4].
• However, how the expanded polyglutamine repeats of mutant huntingtin cause HD is not known [25].
• Interestingly, like the in vitro aggregates, aggregates from HD brain display Congo red staining with green birefringence characteristic of amyloid [26].
• We previously identified a protein (HAP1) which binds to huntingtin in a glutamine repeat length-dependent manner [27].
• Huntingtin phosphorylation on serine 421 is significantly reduced in the striatum and by polyglutamine expansion in vivo [28].

Physical interactions of HD

• Additionally, an anti-SH3GL3 antibody was also able to coimmunoprecipitate the full-length huntingtin from an HD human brain extract [29].
• Cdc42-interacting protein 4 binds to huntingtin: neuropathologic and biological evidence for a role in Huntington's disease [3].
• PACSIN 1 interacts with huntingtin and is absent from synaptic varicosities in presymptomatic Huntington's disease brains [24].
• Further, truncated huntingtin coimmunoprecipitated with tTG, and this association increased when tTG was activated [25].
• The repertoire of huntingtin-interacting proteins continues to expand with the identification of HIP1, a protein whose yeast homologues have known functions in regulating events associated with the cytoskeleton [30].

Enzymatic interactions of HD

• Here we show that apoptotic extracts and apopain itself specifically cleave the HD gene product, huntingtin [18].
• We show that SGK phosphorylates huntingtin at serine 421 and that phosphorylation can protect striatal neurons against polyQ-huntingtin-induced toxicity [16].
• Expression of polyglutamine-expanded huntingtin induced elevation of phosphorylated or activated Src and increased targeting of PSD-95 (post-synaptic density 95) and activated Src to cell surface membrane [31].
• We examined normal and Huntington's disease (HD) human striatum with specific monoclonal antibodies to nonphosphorylated (SMI 32) and phosphorylated (SMI 31) neurofilament and neural cell adhesion molecule (NCAM) [32].
• The breakage has occurred between D4S43 and D4S90 loci and thus deletes part of the chromosomal candidate regions for the HD locus [33].

Co-localisations of HD

• In contrast, in cells expressing truncated mutant huntingtin (Q62) there were numerous complexes of truncated mutant huntingtin and many of these complexes co-localized with tTG [25].
• Our laboratory previously demonstrated that huntingtin protein colocalizes with transglutaminase 2 and its product, the epsilon-(gamma-glutamyl)lysine bond in intranuclear inclusions in HD frontal cortex [34].

Regulatory relationships of HD

• In the striatum, huntingtin is expressed in 75% of neurons containing BDNF [35].
• When a YFP-tagged mutant truncated huntingtin construct was transiently transfected into cells that express no detectable tTG due to stable transfection with a tTG antisense construct, there was extensive aggregate formation [36].
• However, in addition to CBP recruitment, we show here that CBP ubiquitylation and degradation can be selectively enhanced by polyQ-expanded htt [37].
• The serum- and glucocorticoid-induced kinase SGK inhibits mutant huntingtin-induced toxicity by phosphorylating serine 421 of huntingtin [16].
• In our previous studies, we found that expression of polyglutamine-expanded huntingtin in HN33 cells induced sensitization of N-methyl-D-aspartate (NMDA) receptors (Sun, Y., Savinainen, A., and Liu, Y. F. (2001) J. Biol. Chem. 276, 24713-24718) [31].

Other interactions of HD

• Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract [18].
• SH3GL3 associates with the Huntingtin exon 1 protein and promotes the formation of polygln-containing protein aggregates [29].
• Marked CIP4 overexpression also was observed in Western blot from human HD brain striatum [3].
• Using the yeast two-hybrid system, we have isolated a novel htt interacting protein, HIP14 [38].
• Furthermore, this interaction is repeat-length-dependent and is enhanced with mutant huntingtin, possibly causing the sequestration of PACSIN 1 [24].

Analytical, diagnostic and therapeutic context of HD

• HAP1 localization was also determined in human postmortem tissue from control and Huntington's disease (HD) cases by light microscopic immunocytochemistry [39].
• Truncated forms of Htt, which are similar to the caspase-cleaved products in size, exist in the nucleus of HD patient and animal model brains [20].
• Since none of the genes already included in the differential diagnosis of HD was responsible for the disease in our sample, the genetic heterogeneity of the HDL phenotype is still open for investigation [40].
• In cell cultures and in YAC transgenic mice, the endogenous phosphorylation of polyglutamine-expanded htt is significantly reduced relative to wild-type htt [28].
• Immunofluorescence showed that transfected HAP1 colocalized with P150 and huntingtin in human embryonic kidney (HEK) 293 cells [41].

References