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前言 Introduction
亨廷顿氏病,也被称为亨廷顿舞蹈病,或障碍(HD),是一种无法治愈的神经退行性遗传性疾病,其特征是纹状体神经元的损失,影响肌肉协调，还相应的造成知识能力的损害,情感上的障碍,以及认知功能的伤害。这是最常见的异常的遗传原因，不随意肌运动称为舞蹈病。退化的神经元影响基底神经节细胞,这是因为大脑深处结构有许多重要的功能,包括协调运动。在基底神经节中,血液透析将纹状体神经元作为目标。血液透析也会影响大脑的外表面,或皮层,控制思想,认知,和记忆。
这种疾病是由显性突变引起的，一个特定基因有两个副本,位于染色体4。任何受父母遗传影响的孩子得这种疾病的风险为50%。在极少数情况下,父母双方有一个受影响的基因,或父母任意一方有两个受影响的基因副本,这种风险就会大大增加。
Huntington's disease, also known as huntington chorea, or disorder (HD), is an incurable neurodegenerative genetic disorder characterized by loss of striatal neurons that affects muscle coordination, loss of intellectual faculties, and emotional disturbance, as well as impairment of some cognitive functions. It is the most common genetic cause of abnormal involuntary muscle movements called chorea. Degeneration of neurones specifically affects cells of the basal ganglia, which are structures deep within the brain that have many important functions, including coordinating movement. Within the basal ganglia, HD targets neurons of the striatum. HD also affects the brain's outer surface, or cortex, which controls thought, perception, and memory.
The disease is caused by a dominant mutation on either of the two copies of a specific gene, located on chromosome 4. Any child of an affected parent has a 50% risk of inheriting the disease. In rare situations where both parents have an affected gene, and either parent has two affected copies, this risk is greatly increased.
Physical symptoms of Huntington's disease can begin at any age from infancy to old age, but usually begin between 35 and 44 years of age. On rare occasions, when symptoms begin before about 20 years of age, they progress faster and vary slightly, and the disease is classified as juvenile, akinetic-rigid or Westphal variant HD. HD-HTT gene
The HD mutation was found in 1993 as an unstable expansion of the CAG (trinucleotide) repeat within the coding region of the gene "IT15". This gene on chromosome 4 (4p63), encodes the protein, Huntington (htt). HD is thought to have been caused by the tri-nucleotide repeat in the Huntington gene which translates as a polyglutamine (polyQ) repeat in the protein product.
Htt gene is a 348-kDa multidomain protein that contains a polymorphic glutamine/ proline-rich domain at its amino-terminus. The longer polyQ domain seems to induce conformational changes in the protein, which causes it to form intracellular aggregates that, in most cases, manifest as nuclear inclusions. However, aggregates can also form outside the nucleus. Despite its large size, the normal function of htt has been difficult to establish because it contains very little sequence homology to other known proteins, is ubiquitously expressed and is localized in many subcellular compartments (The hunt for huntingtin function - Harjes & Wanker, 2003).
Htt is present in the nucleus, cell body, dendrites and nerve terminals of neurons, and is also associated with a number of organelles including the Golgi apparatus, endoplasmic reticulum and mitochondria. Various approaches have been used to determine the function of htt and its pathological effects, and it is becoming Apparent that the role of htt is complex and that it operates at many different cellular levels (Harjes & Wanker, 2003). Htt forms part of the dynactin complex, co-localizing with Microtubules and interacting directly with β-tubulin, which suggests a role in vesicle transport and/or cytoskeletal anchoring. Interestingly, htt has also been shown to have a role in clathrin-mediated endocytosis, neuronal transport and postsynaptic signalling. Furthermore, htt can protect neuronal cells from apoptotic stress and therefore may have a pro-survival role. Pathogenesis of Huntington’s Disease
The cAMP-responsive element pathway and the SP1 pathway.
Of the transcription pathways that are affected in HD, the cAMP- responsive element (CRE) - and the SP1-mediated pathways are widely studied. (Fig 1A. Description of the CRE pathway).
The ablation of CREB results in an HD-like phenotype in mice, in which there is progressive neurodegeneration in the hippocampus and striatum (Disruption of CREB function in brain leads to neurodegeneration - Mantamadiotis et al, 2002), and the down-regulation of CRE-regulated genes has also been detected in HD patients. The CRE pathway initially focused on CBP, which is sequestered into aggregates, and which led to the proposal that the availability of CBP for CRE-mediated transcription is disrupted (Huntingtin-protein interactions and the pathogenesis of Huntington's disease - Li & Li, 2004).
However, CBP can be sequestered into aggregates formed by several other polyQ proteins, including atrophin 1(protein found in nervous tissue, associated with a form of Trinucleotide repeat disorder), the androgen receptor (DNA binding receptor which regulates gene expression) and ataxin3 (in Machado-Joseph disease also known as spinocerebellar ataxia-3).
Htt has been shown to interact with CBP through both its glutamine-rich and acetyltransferase domains; this may account for the observed decrease in CRE-mediated transcription and the loss of acetyltransferase activity seen in polyQ models of disease.
A study by Obrietan & Hoyt in 2004 on CRE-mediated transcription is in Huntington's disease reported that CRE-dependent transcription is upregulated in double-transgenic mice expressing mutant htt and a CRE-β- galactosidase reporter construct. Moreover, phosphorylated CREB levels were also elevated, as were the levels of the CREB-regulated gene product CCAAT-enhancer binding protein, which suggests that mutant htt facilitates CRE-dependent transcription. In addition to CBP, CRE-mediated transcription also appears to be affected by the coactivator TAFII130. This coactivator has also been found in aggregates and, on over-expression, inhibition of CREB dependent transcription can be overcome (Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription - Shimohata et al, 2000). Fig 1. Description of the CRE pathway
Htt is a multi-domain protein with many functions, including transcriptional regulation, intracellular transport and involvement in the endosome–lysosome pathway. The protein also has pro-survival properties.
The chromosomal position of the Huntington gene is large, spanning 180 kb and consisting of 67 exons. The Huntington gene is widely expressed and is required for normal development. It is expressed as 2 alternatively polyadenylated forms displaying different relative abundance in various fetal and adult tissues. The larger transcript is approximately 13.7 kb and is expressed predominantly in adult and fetal brain whereas the smaller transcript is 10.3 kb and is more widely expressed. The genetic defect leading to Huntington disease may not necessarily eliminate transcription, but may alter the function of the protein. Location of HTT Gene:
Figure1. The HTT gene is located on the short arm (p) of chromosome 4 at position 4p16.2. More precisely, the HTT gene is located from base pair 3,046,205 to base pair 3,215,484 on c-some 4. Expansion of PolyQ
The mutation in Huntington produces an expanded stretch of glutamine residues attached to its amino terminal. Expansions beyond a threshold of 36 CAG's at 5’ end of the transcript encoding huntingtin cause Huntington’s disease. This mutation increases the size of the CAG segment in the htt gene. People with Huntington disease have 36 to more than 120 CAG repeats. People with 36 to 40 CAG repeats may or may not develop the signs and symptoms of Huntington disease, while people with more than 40 repeats almost always develop the disorder.
The expanded CAG segment leads to the production of an abnormally long version of the Huntingtin protein. The lengthened protein is cut into smaller, toxic fragments that bind together and accumulate in neurons, disrupting the normal functions of these cells. This process particularly affects regions of the brain that help coordinate movement and control thinking and emotions (the striatum and cerebral cortex). The dysfunction and eventual death of neurons in these areas of the brain underlie the signs and symptoms of Huntington disease.
A larger number of repeats are usually associated with an earlier onset of signs and symptoms. This phenomenon is called anticipation. People with the adult-onset form of Huntington disease (which appears in mid-adulthood) typically have 40 to 50 CAG repeats in the HTT gene, while people with the less common, early-onset form of the disorder (which appears in childhood or adolescence) tend to have more than 60 CAG repeats. Individuals who have 27 to 35 CAG repeats in the HTT gene do not develop Huntington disease, but they are at risk of having children who will develop the disorder. As the gene is passed from parent to child, the size of the CAG trinucleotide repeat may lengthen into the range associated with Huntington disease (36 repeats or more). |
