What Is Polyglutamine?

The research on the pathogenesis of polyglutamine disease is currently a hot topic at home and abroad. Its pathogenesis is caused by the nucleation of mutant proteins. According to the data of the Human Genome Project, it is believed that the earliest cause was primitive humans receiving dogs. ^[1] Burr Norovirus infection. The excessive repeat of the first three amino groups of the DNA of the spermatogonial stem cells is related to the fact that although pathogenic proteins are widely expressed in the central nervous system, each disease has a specific susceptible neuron population, thus Different forms of neurodegeneration and disease phenotype

Polyglutamine disease

Research on the pathogenesis of polyglutamine disease is currently a hot topic at home and abroad, and its pathogenesis is due to the mutation of the protein

The repeat of the first two bases of the three bases of CAG in the coding region encodes polyglutamine, which is a translation of two out of three in the gene description. The series of diseases caused by this are called polyglutamine diseases. (Polyglutamine disease, polyQ disease), currently such diseases include the above 7 autosomal dominant ataxias, and Huntington's disease (Huntington disease, HD) (the earliest cause is believed to be the original human infection with canine Bernard The excessive duplication of CAG caused by spermatogonial stem cells is related to spinal and bulbar muscular atrophy (Kennedy's Syndrome, SBMA). The abnormal CAG repeat sequence of PolyQ disease has a growing trend, leading to the onset of the offspring's age earlier than the father's, and the course of the disease progresses rapidly, which is called the early genetic phenomenon. Unlike fragile X syndrome, tonic muscular dystrophy, and Friedreich's ataxia (FRDA), a large trinucleotide repeat expansion, the number of abnormal trinucleotide repeats in polyglutamine diseases is mostly about 40 to 130. .

The research on the pathogenesis of polyglutamine disease is currently a hot topic at home and abroad. Its pathogenesis is caused by the nucleation of mutant proteins. According to the data of the Human Genome Project, it is believed that the earliest cause was primitive humans receiving dogs. ^[1] Burr Connaught infection. The excessive repeat of the three-letter amino group of the DNA of the spermatogonial stem cells is related. Although the pathogenic protein is widely expressed in the central nervous system, each disease has a specific susceptible neuron population, thus The forms and phenotypes that cause neurodegeneration vary. The current research on the pathogenesis focuses on the following four aspects:

Abnormal aggregation of proteins

The accumulation of mutant proteins to form insoluble aggregates is a common feature of polyglutamine diseases, where SCA1, SCA7, and SCA17 are intranuclear aggregates, SCA2 and SCA6 are cytoplasmic aggregates, and HD, DRPLA, SBMA, and SCA3 are aggregated. Aggregation occurs in both the nucleus and the cytoplasm. The mutant proteins aggregate to form inclusion bodies, which also include molecular chaperones and components of the ubiquitin proteasome system, indicating that the extended glutamine chain changes the conformation of the protein and initiates cellular defense mechanisms to resist the abnormal folding of the protein. Studies have shown that the degree of lesions in the SCA7 susceptible cell population is inversely proportional to the number of nuclear inclusions formed by ataxin7, indicating that the inclusions play a protective role in the occurrence of disease. This view has been increasingly supported.

Transcription and post-transcriptional mechanisms

The nuclear localization of mutant proteins is critical in the pathogenesis of most polyglutamine diseases, and transcriptional changes precede the appearance of phenotypes in some disease models. These two points indicate that abnormal regulation of transcription is in the pathogenesis. makes an important impact. These abnormal regulatory effects may be mediated by several mechanisms. Polyglutamine can interact with several transcription regulators, including CREB-connexin (Cyclic AMP Response Element-Binding Protein-binding protein, CREBBP, CBP), TAFII130 (TBP-related factor), SP1 transcription factor and P53, Some of these molecules are also found in polyglutamine inclusion bodies. In some polyglutamine disease models, CBP is not contained in the inclusion body, and transcriptional changes occur before inclusion bodies appear, suggesting another mode of polyglutamine toxicity, namely the toxicity of soluble non-aggregated forms of proteins effect. Some polyglutamine disease-causing genes encode proteins that are related to transcription. The SCA17 gene encodes TBP, and the SBMA gene encodes the androgen receptor. Huntingtin may play a transcriptional co-operation by interacting with a complex containing a co-inhibitory protein in the nucleus. The function of repressor (co-repressor), atrophin1, ataxin3 and ataxin1 also have the function of transcription regulation. The regulation of chromatin may be another aspect of polyglutamine-mediated transcription regulation. Histone deacetylase inhibitors can reduce the toxicity of mutant polyglutamine proteins in cultured cells and animal models.

Intracytoplasmic anomaly

Mutated polyglutamine proteins can also affect the functions of components in the cytoplasm, such as axonal transport and mitochondrial function. Reduction of Huntingtin and abnormal expression, as well as the extended polyglutamine fragment of ataxin3 can hinder axonal transport. The abnormal huntingtin in HD can affect calcium signal transmission through the cooperation of several mechanisms, including the effect on mitochondria. In addition, the extended polyglutamine protein is cleaved in the cytoplasm by cysteinyl aspartate specific protease (Caspases) and cysteine protease calpains. A series of downstream events such as misfolding and effects on transcription.

Role of non-polyQ domains in mutant proteins

It has been relatively clear that the overall abnormal function of the mutant protein is very important in the pathogenesis. Regulation outside the polyglutamine domain, such as phosphorylation of an important serine, such as ataxin1, plays a crucial role in the development of mutein toxicity. Wild-type ataxin3 has ubiquitin protease activity and inhibits polyglutamine-mediated neuronal degeneration, while wild-type and mutant ataxin7 can affect transcription through interaction with the STAGA / TFTC complex. Polyglutamine proteins have their own specific functions, and these functions will be affected after the polyglutamine chain extension mutation in the protein.