Huntingtin Comparative Pathway
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Huntingtin Comparative Pathway

Huntington disease is an Autosomally Dominant degenerative disorder resulting from expansion (>37 units) of a polyglutamine repeats in Huntingtin, a 350-kDa protein of unknown function. The polyglutamine repeat is localized in the N-terminal region of Huntingtin and is encoded by exon1 of the HD or Htt (Huntingtin) gene. Huntington disease is characterized by uncontrolled movements, personality changes, and dementia and causes the death of patients within 10-20 years after the appearance of the first symptoms. Huntingtin is highly expressed in the brain, and particularly enriched in Cerebral Cortex and Striatum. It is a cytoplasmic protein that is essential during development for Gastrulation and Neurogenesis, and it is important for Neuronal survival in the adult. Wild-type Huntingtin is anti-apoptotic in neurons in the Central Nervous System. Wild-type Huntingtin also reduces the toxicity of mutant Huntingtin in vivo. Huntingtin is also involved in vesicle trafficking in the secretory and endocytic pathways (Ref.1).

Huntingtin shuttles between the nucleus and the cytoplasm. Full-length Huntingtin is predominantly distributed in the cytoplasm, whereas N-terminal fragments of Huntingtin with expanded polyglutamine tracts accumulate in the nucleus. Alternate Huntingtin conformations, are associated with cytoplasmic speckles and nuclear speckles or with perinuclear membranes and nucleoli. Moreover, its front end can associate with dozens of signal transduction proteins. This cargo includes members of transcription complexes [basal transcription factors (for example, SP1, TAFII130 (TBP-Associated Factor, RNA Polymerase II)), transcriptional co-repressors and co-activators (for example, NCOR1 (Nuclear Receptor Co-Repressor-1), Sin3A, CTBP (C-Terminal-Binding Protein), REST (RE1-Silencing Transcription Factor), p53), spliceosome and polyadenylation factors (for example, FBP11, symplekin)], a ubiquitin protein ligase (E2-25 kD) that regulates transcription factor turnover, effectors [receptors (for example, NMDAR (N-methyl-D-aspartate calcium channel receptors), EGFR (Epidermal Growth Factor Receptor)), Kinase (MLK2 (Mixed Lineage Kinase-2)), and Phosphatase (SHP2)], and adaptor proteins that localize signaling complexes (for example, GRB2 (Growth Factor Receptor-Bound Protein-2), PACSIN1 (Protein Kinase-C and Casein Kinase Substrate in Neurons-1), PSD95 (Postsynaptic Density-95), HAP1 (Huntingtin’s associated protein-1). Huntington disease pathogenesis can be viewed as a cascade of events that is first triggered by mutant Huntingtin through an abnormal interaction with an as-yet unknown cellular constituent. Once triggered, this cascade broadens with time, leading eventually to neuronal cell death (Ref.2).

The Huntingtin’s expanded polyglutamine alters protein conformation, resulting in aberrant protein interactions, including interactions of the expanded polyglutamine with cellular proteins containing short polyglutamine stretches. CBP (CREB Binding Protein) is a co activator for CREB (cAMP Response Element-Binding Protein)-mediated transcription and contains an 18-glutamine stretch. CREB-mediated gene transcription promotes cell survival, and CBP is a major mediator of survival signals in mature neurons. CBP is a large protein with multiple domains and in addition to interacting with several different transcription factors also has a Histone Acetylase enzyme activity. The expanded polyglutamine in HD can interact with the short glutamine repeat in CBP, interfering with CBP function, causing transcriptional abnormalities, and leading to cellular toxicity. Mutant Huntingtin binds to CBP, drawing it into insoluble protein aggregates. Mutant Huntingtin also interacts directly with the acetyltransferase domain of CBP, blocking this activity. Activation of CBP acetyltransferase activity by transcriptional regulators results in the acetylation of histones in the promoter and enhancer regions of active genes, contributing to transcriptional activation by making these genes more accessible in chromatin. The lack of CBP in Huntingtons affected neurons may lead to transcriptional repression of key genes that in turn leads to neurodegeneration (Ref.3).

Huntingtin’s association with REST (Repressor Element-1 Transcription Factor) also enhances transcriptional derepression of NRSE (Neuron Restrictive Silencer Element)-regulated target genes. These genes encode a broad range of proteins involved in neuronal function and development and include neurotransmitter receptors; neurotrophins, such as BDNF (Brain-Derived Neurotrophic Factor); synaptic vesicle proteins; cytoskeletal proteins; growth factors; and ion channels. Wild-type Huntingtin, but not expanded repeat mutant Huntingtin, stimulates transcription of the gene encoding BDNF. The BDNF promoter contains an NRSE. REST/NRSF (Neuron-Restrictive Silencer Factor) binds mammalian Sin3A (Sin3 Homolog-A Transcriptional Regulator) and HDAC2 (Histone Deacetylase-2) and requires Histone Deacetylase activity to repress neuronal gene transcription. CoREST functions as an additional corepressor for REST. Wild-type Huntingtin was found to interact with REST/NRSF and, furthermore, be required to keep REST/NRSF in the cytosol, thereby preventing the formation of the corepressor complex and allowing neuronal expression of the gene. In Huntington disease, neuronal genes with NRSEs, such as BDNF and Penk (encoding Proenkephalin), are expressed at lower levels owing to the presence of mutant Huntingtin instead of two intact copies of wild-type Huntingtin. Without normal levels of wild-type Huntingtin available to bind REST/NRSF in the cytosol, more of this silencing factor can enter the nucleus to repress transcription (Ref.4).

 Mutant Huntingtin also disrupts transcriptional activation by SP1 and TAFII130 in HD. The transcription factor SP1 binds to DNA elements called GC boxes in cellular promoters. A specific protein-protein interaction between the glutamine-rich regions of SP1 and the TAFII130 subunit of TFIID (Transcription Factor-IID) is required for recruitment of the general transcriptional machinery, which includes transcription factors TFIIA (Transcription Factor-IIA), TFIIB (Transcription Factor-IIB), TFIID, TFIIE (Transcription Factor-IIE), TFIIF (Transcription Factor-IIF), and TFIIH (Transcription Factor-IIH). This glutamine interface serves to bridge SP1 to the machinery required to recruit RNA Pol II (Polymerase (RNA) II (DNA directed)). Once correctly targeted to the dopamine D2 receptor gene, RNA Pol II initiates transcription of an mRNA copy of this gene. In HD, the glutamine expansion in Huntingtin disrupts transcriptional activation by SP1 and TAFII130. The mutant Htt associates with SP1 and TAFII130, preventing SP1 from binding to the GC box, and ultimately disrupting the ability of SP1 and TAFII130 to interact. Without proper targeting by the general transcriptional machinery, RNA Pol II cannot properly locate the Dopamine D2 receptor promoter region and the gene cannot be transcribed. The deregulated expression of this gene, as well as of many others, may be an early step in the neurodegenerative process-taking place in the HD brain (Ref.5).

Under normal circumstances, Htt also heterodimerize with HIP1 (Huntingtin Interacting Protein-1). HIP1 directly associates with Clathrin heavy chain as well as Alpha-Adaptin A and C. These proteins are major components of Clt (Clathrin)-coated vesicles and are important for receptor-mediated endocytosis at the Plasma membrane. The HIP1-Huntingtin heterodimer is involved in exocytosis of neurotransmitter. Increase in the size of the polyglutamine repeat reduces the interaction with Huntingtin and HIP1. Free HIP1 can bind to HIPPI (HIP1 Protein Interactor). The HIP1/HIPPI heterodimer can recruit and activate Procaspase8, leading to apoptosis of the neuron (Ref.6).  Thus it is found that Huntingtin has an important constitutive role in neurons during brain development, that heterogeneity in neuronal expression of the protein is developmentally regulated, and that the intraneuronal distribution of Huntingtin increases in parallel with neuronal maturation. The presence of mutant Huntingtin in the immature HD brain raises the possibility that neurons may be affected during brain development and possibly in the postnatal period when vulnerability to excitotoxic injury is at its peak (Ref.1 & 7).