Disease relevance of Hdh

• The three approaches consistently yielded reduced levels of Sp1 which ameliorated toxicity caused by either mutant Htt or 3-NP [1].
• Huntington's disease (HD) is an autosomal dominant neurological disorder characterized by progressive chorea, cognitive impairment and emotional disturbance [2].
• Trophic factor administration has emerged as a compelling potential therapy for a variety of neurodegenerative disorders, including HD [3].
• Our data suggest that the different physiological responses induced by the activation of ionotropic glutamate receptors may account for the cell type-specific vulnerability of striatal neurons in ischemia and HD [4].
• We established stably transfected pheochromocytoma PC12 cells that express the N-terminal fragment of huntingtin containing 20 (20Q) or 150 (150Q) glutamine residues [5].

Psychiatry related information on Hdh

• Interactions between mutant huntingtin (Htt) and a variety of transcription factors including specificity proteins (Sp) have been suggested as a central mechanism in Huntington disease (HD) [1].
• Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by chorea, psychiatric disturbances, and dementia [6].
• Huntington's disease (HD) patients show severe diurnal choreic movements, while during slow-wave sleep (SWS) abnormal movements subside [7].
• The observation of these two types of locomotor activity is unique since no excitotoxin model has replicated a two-stage progression of a HD-like behavioral alteration [8].

High impact information on Hdh

• We have used RNA in situ hybridization to study the regional expression of the Huntington's disease gene (HD) and its rat homologue in brain and selected nonneural tissues [9].
• The regional specificity of neuropathology in HD, which is most prominent in the basal ganglia, thus cannot be accounted for by the pattern of expression of HD [9].
• HD mRNA was also expressed in colon, liver, pancreas and testes [9].
• The HD transcript was expressed throughout the brain in both rat and human, especially in the neurons of the dentate gyrus and pyramidal neurons of the hippocampal formation, cerebellar granule cell layer, cerebellar Purkinje cells and pontine nuclei [9].
• Schwarcz and colleagues have shown that quinolinic acid (QA) can produce axon-sparing lesions similar to those observed in HD [2].

Chemical compound and disease context of Hdh

• Huntington's disease (HD) is caused by a polyglutamine expansion in the amino-terminal region of huntingtin [10].
• Quinolinic acid (QA) is an endogenous excitotoxin present in mammalian brain that reproduces many of the histologic and neurochemical features of Huntington's disease (HD) [11].
• Stereotaxic injection of kainic acid into rat striatum produces neuronal degeneration and neurochemical alterations resembling Huntington's disease (HD) [12].
• Oral supplementation with creatine or cyclocreatine results in neuroprotective effects in vivo, which may represent a novel therapeutic strategy for HD and other neurodegenerative diseases [13].
• Huntington's disease is one of a growing number of hereditary neurodegenerative disorders caused by expansion of a polyglutamine stretch at the NH2 terminus of huntingtin [14].

Biological context of Hdh

• In the current study, we characterized the relationship of Sp1 to Htt protein aggregation and neuronal cell death [1].
• Downregulation of HIP14 in mouse neurons expressing wild-type and mutant htt increases inclusion formation, whereas overexpression of HIP14 substantially reduces inclusions [15].
• Five out of nine compounds tested in an Htt exon 1 assay of neurodegeneration in Drosophila partially rescued the phenotype [16].
• Huntington's disease (HD) is a fatal, genetic, neurological disorder resulting from a trinucleotide repeat expansion in the gene that encodes for the protein huntingtin [3].
• The gene defect in Huntington's disease (HD) may result in an impairment of energy metabolism [13].

Anatomical context of Hdh

• We found increased levels of Sp1 in neuronal-like PC12 cells expressing mutant Htt, primary striatal neurons, and brain tissue of HD transgenic mice [1].
• These findings suggest that HAP1 trafficking is critical for the stability of TrkA and neurite function, both of which can be attenuated by mutant huntingtin [17].
• The lowest levels of HAP1 mRNA expression corresponded with the areas of greatest pathological cell loss in Huntington's disease (HD); the caudate putamen, globus pallidus and neocortex [18].
• These results suggest that the expansion of the polyglutamine tract in htt results in decreased palmitoylation, which contributes to the formation of inclusion bodies and enhanced neuronal toxicity [15].
• Somatostatinergic striatal interneurons, which are medium in size, rarely contained huntingtin [19].

Associations of Hdh with chemical compounds

• Exposure of primary neurons to glutamate or 3-nitropropionic acid increases intracellular calcium concentration, leading to loss of intact full-length wild-type huntingtin [10].
• These findings suggest that especially an increased amount of monomeric form of small N-terminal mutant huntingtin fragments may facilitate aberrant interactions both with itself via the polyglutamine stretch and with other proteins and thereby contribute to molecular pathogenesis [20].
• Here we show that huntingtin (htt) is normally palmitoylated at cysteine 214, which is essential for its trafficking and function [15].
• The palmitoylation and distribution of htt are regulated by the palmitoyl transferase huntingtin interacting protein 14 (HIP14) [15].
• Malonate and 3-nitropropionic acid (3-NP) are inhibitors of succinate dehydrogenase that produce energy depletion and lesions that closely resemble those of HD [13].

Physical interactions of Hdh

• Mutant huntingtin bound much stronger to CBP than normal huntingtin, possibly contributing to repression [21].

Regulatory relationships of Hdh

• Mutant huntingtin represses CBP, but not p300, by binding and protein degradation [21].
• alpha-synuclein overexpression promotes aggregation of mutant huntingtin [22].

Other interactions of Hdh

• Huntingtin is degraded to small fragments by calpain after ischemic injury [23].
• Pax6 is a HD protein that has previously been shown to be involved in the differentiation of the hindbrain somatic (SM) motoneurones and V1 interneurones in the hindbrain and/or spinal cord [24].
• Thus, mutant huntingtin specifically affects CBP and not p300 both at the early and later time points, via multiple mechanisms [21].
• Our data showed that striatopallidal neurons co-containing SP and D1a [Surmeier, D.J., Song, W.J., and Yan, Z., J. Neurosci., 16 (1996) 6579-6591] co-localized with huntingtin in a higher proportion than striatonigral neurons [25].
• Calbindin-containing projection neurons of the matrix compartment and calbindin-negative projection neurons of the striatal patch compartment contained huntingtin with comparable frequency [19].

Analytical, diagnostic and therapeutic context of Hdh

• We examined htt expression by Western blot in the rat brain after transient ischemic injury, which causes striatal neurodegeneration similar to that seen in HD and activates proteases including calcium-dependent calpains [23].
• It is concluded that (1) the QA animal model of HD mimics some of the SEP abnormalities of patients, and (2) a striatal lesion modulates somatosensory transmission to the cortex in rats [26].
• Immunohistochemistry and single-cell RT-PCR were used to characterize the localization of huntingtin and/or its mRNA in the major types of striatal neurons and in corticostriatal projection neurons in rats [19].
• By double-label immunofluorescence, huntingtin was nonselectively expressed in virtually all striatal neurons including SS/NPY/NADPH-d neurons [27].
• Neural progenitor transplantation is a potential treatment for neurodegenerative diseases, including Huntington's disease (HD) [28].

References