Huntington's Disease Pathway
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Huntington's Disease Pathway
Huntingtons disease, also known as Huntington Chorea, is a dominantly inherited Neurodegenerative disorder featuring progressively worsening Chorea, Psychiatric disturbances and Cognitive Impairment due to neuronal cell loss in the Basal ganglia and the Cerebral cortex. It affects about one in 10,000 individuals and is transmitted in an Autosomal dominant fashion. George Huntington, an American physician, first documented Huntington’s in 1872. Huntington’s disease is caused by an abnormal polyglutamine extension of a 350-kDa protein named Huntingtin. The IT15 or Htt (Huntingtin) gene responsible for the disease, located on chromosome 4, enables the synthesis of the HD (Huntingtin) protein. Large polyglutamine repeats in the Huntingtin protein is the genetic defect responsible for this condition, caused by expansion of a polymorphic CAG trinucleotide repeats in the gene. The CAG repeat is polymorphic in the normal population, with a length of 8-39 repeats, but in Huntingtons disease patients has 36-121 repeats. The polyglutamine repeat makes Huntingtin protein insoluble and triggers the formation of protein aggregates (Ref.1).

Huntingtin is expressed ubiquitously, with the highest levels found in the brain, particularly in cortical layers II and V and in the Cerebellar Purkinje cells and both the normal and expanded alleles are expressed in HD. Wild-type Huntingtin is cleaved and stays in the cytoplasm. The mutation causes a conformational change and abnormal folding of the protein, which can be corrected by molecular chaperones. Mutant Huntingtin has effects both in the cytoplasm and in the nucleus. Alternate Huntingtin conformations, are associated with cytoplasmic speckles and nuclear speckles or with perinuclear membranes and nucleoli. Mutant Huntingtin can also undergo proteolytic cleavage, both in the cytoplasm and in the nucleus. The N terminus with the expanded repeat can assume a Beta sheet structure. Toxicity in the cytoplasm may involve soluble monomers or oligomers or possibly insoluble aggregates, via inhibition of the proteasome or activation of Caspases directly or via mitochondrial effects. Cytoplasmic aggregates accumulate in perinuclear or neuritic regions and are ubiquitinated. The mutant protein translocates to the nucleus, where its effects are dual. Mutant Huntingtin enters the nucleus through pores, losing its antiapoptotic function and generating toxic products. So Huntingtons disease is both a gain of function through the generation of polyglutamine fragments, and a loss of antiapoptotic function (Ref.2 & 3). Moreover, Huntingtin can also associate with dozens of signal transduction proteins. This cargo includes members of transcription complexes (basal transcription factors (for example, SP1 (Transcription Factor SP1), TAFII130 (TBP-Associated Factor, RNA Polymerase II ), transcriptional Co-repressors and Co-activators (NCOR1 (Nuclear Receptor Co-Repressor-1), Sin3A (Sin3 Homolog-A Transcriptional Regulator), CTBP(C-Terminal-Binding Protein), REST (RE1-Silencing Transcription Factor), CoREST, HDAC2 (Histone Deacetylase-2), p53, Spliceosome and Polyadenylation factors (Fbp11, Symplekin), a Ubiquitin protein ligase (E2-25 kD) that regulates transcription factor turnover, effectors, receptors ((NMDAR (N-methyl-D-Aspartate calcium channel Receptor), EGFR (Epidermal Growth Factor Receptor)), Kinase (MLK2 (Mixed Lineage Kinase-2)), and Phosphatase (SHP2) and adaptor proteins that localize signaling complexes ( 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)) (Ref.4 & 5).

Mitochondria also play an important role in Huntingtons disease pathology. Apoptotic stress induces mitochondrial depolarization in Huntingtons disease lymphoblasts. This leads to overactivation of Caspase3, which is capable of cleaving Htt. Truncated forms of mutant Htt accumulate in the nucleus and are toxic to cells. Truncated forms of mutant Htt in the nucleus influence gene transcription by binding to proteins such as CBP (CREB Binding Protein), NCOR, GAPDH (Glyceraldehyde-3-Phosphate Dehydrogenase), and p53. Htt entangles and inhibits CBP, a smaller regulatory protein that is key for cell survival. CBP has its own tract of 18 Glutamines, and these glutamines interact directly with the expanded Htt Glutamine chain. Huntingtin aggregates pull CBP away from its normal position alongside the DNA in the nucleus. Once seized, CBP is out of service. It can no longer accomplish its normal function of activating transcription or turning on genes for survival pathways. Fewer proteins are produced, ultimately leading to nerve cell death. Htt also binds to p53. p53 regulates the transcription of various mitochondrial proteins, which may underlie the mitochondrial abnormalities, especially the vulnerability to mitochondrial depolarization, seen in HD tissues (Ref.6).

In the brain, Huntingtin protein also interacts with two other proteins, HIP1 (Huntingtin’s Iinteractor Protein-1) and HAP1. The number of C-A-G repeats in the Huntingtin gene determines how the Huntingtin protein interacts with HIP1 and HAP1. As repeat numbers increase, Huntingtin binds less to HIP1 and more to HAP1. Free HIP1 binds to a hitherto unknown polypeptide, HIPPI (HIP1 Protein Interactor), which has partial sequence homology to HIP1 and similar tissue and subcellular distribution. The availability of free HIP1 is modulated by polyglutamine length within Htt, with disease-associated polyglutamine expansion favouring the formation of pro-apoptotic HIPPI-HIP1 heterodimers. This heterodimer can recruit Procaspase8 into a complex of HIPPI, HIP1 and Procaspase8, and launch apoptosis through components of the Extrinsic cell-death pathway (Ref.6). N terminus of Huntingtin, together with HAP1, also enhances the activation of the neuronal cell transcription factor NeuroD by the Huntingtin partner, MLK2. The interaction of Huntingtin with HAP1 is polyglutamine length dependent, as are Huntingtin interactions with GAPDH and Calmodulin. Huntingtin-HAP1 complexes also stimulate IP3 (Inositol 1,4,5-Trisphosphate) activation of the calcium release channel IP3R (IP3 Receptor), a key player in intracellular Ca2+ signaling. Normally, Htt interacts with the NMDAR to increase intracellular Calcium. In the pathogenesis of Huntington’s disease, Mutant Htt has effects on innate Calcium signaling pathways. Mutant Htt further enhances NMDAR function, possibly through an altered interaction with the PSD95 (Postsynaptic Density-95) -NR1A/NR2B complex, and Mutant Htt interacts with the IP3R1 and HAP1 to sensitize the IP3R1. In addition, Mutant Htt increases the amount of IP3 produced by MGluR5 (Metabotropic Glutamate Receptor-5) stimulation via G-Proteins and PLC (Phospolipase-C). PLC lead to the formation of IP3 and DAG (Diacylglycerol). DAG forms PKC (Protein Kinase-C) which activates NMDAR, whereas IP3 helps in calcium release by binding to IP3R. The combination of these effects radically increases the intracellular calcium concentration, which triggers the neuronal apoptotic program. The final outcome of apoptotic program in medium spiny neurons leads to the pathophysiological symptoms of Huntington’s disease. Huntingtin also enhances vesicular transport of BDNF (Brain-Derived Neurotrophic Factor) along microtubules. Huntingtin-mediated transport involves HAP1 and the p150(Glued) subunit of Dynactin, an essential component of molecular motors. The alteration of the Huntingtin/HAP1/p150(Glued) complex correlated with reduced association of motor proteins with microtubules. The polyglutamine-Huntingtin-induced transport deficit resulted in the loss of neurotrophic support and neuronal toxicity (Ref. 7 & 8).

IGF1 (Insulin-like Growth Factor-1)/Akt (v-Akt Murine Thymoma Viral Oncogene Homolog) signaling pathway have a beneficial effect in HD. In striatal neurons, the most vulnerable neurons in HD, IGF1 completely blocks PolyQ-Huntingtin-induced toxicity. This effect is mediated by PI3K (Phosphatidylinositde-3 Kinase), PDK-1 (Phosphoinositide-Dependent Kinase-1), SGK (Serum/Glucocorticoid-Regulated Kinase) and the Serine/threonine kinase Akt, which directly phosphorylates PolyQ-Huntingtin at Ser421, inhibiting the toxic properties of PolyQ-Huntingtin. Akt also acts on other substrates that promote survival by general mechanisms or by mechanisms relevant to HD. The phosphorylation by Akt of substrates other than Htt may be important in the latter stages of the disease. During the pathological process in HD, Huntingtin is cleaved by several proteases, including Caspases , Calpains, and other unidentified proteases. This cleavage generates short N-terminal amino acid fragments that contain the pathological polyglutamine expansion and that are more toxic to neurons than full-length Htt. Some of these short N-terminal fragments do not contain the Ser421 phosphorylation site, suggesting that the direct neuroprotective effect of Akt on Htt is lost during proteolysis. Akt blocks the polyglutamine-dependent neuronal death and inclusion formation that are induced by an N-terminal fragment of Htt that does not contain Ser421. Ser421 Htt-independent mechanism involves the Arfaptin-2 (ADP-Ribosylation Factor-Interacting Protein). Arfaptin-2 is a substrate of Akt and that phosphorylation of Arfaptin-2 by Akt at Ser260 promotes survival of striatal neurons. Arfaptin-2 is involved in the neuroprotective effect of Akt in HD. Arfaptin-2 phosphorylation restores proteasome activity that is inhibited by the presence of polyQ-Htt in cells. Arfaptin-2 regulates aggregate formation of mutant Htt. Once considered a relatively rare disorder, Huntington’s disease has been historically important and continues to be at the frontier of human neurological diseases. Currently HD has no cure or treatment. Scientists are investigating the possibility of developing new therapies that could uncouple the HD gene from potentially harmful interactions. Researchers hope to further decipher HD neurobiology in order to devise therapies that will arrest the disease before it does damage. Furthermore, a better understanding of HD should launch advances in other related triplet repeat disorders (Ref.5, 9 &10).