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atxn1

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Official Full Name
ataxin 1
Background
The autosomal dominant cerebellar ataxias (ADCA) are a heterogeneous group of neurodegenerative disorders characterized by progressive degeneration of the cerebellum, brain stem and spinal cord. Clinically, ADCA has been divided into three groups: ADCA types I-III. ADCAI is genetically heterogeneous, with five genetic loci, designated spinocerebellar ataxia (SCA) 1, 2, 3, 4 and 6, being assigned to five different chromosomes. ADCAII, which always presents with retinal degeneration (SCA7), and ADCAIII often referred to as the `pure cerebellar syndrome (SCA5), are most likely homogeneous disorders. Several SCA genes have been cloned and shown to contain CAG repeats in their coding regions. ADCA is caused by the expansion of the CAG repeats, producing an elongated polyglutamine tract in the corresponding protein. The expanded repeats are variable in size and unstable, usually increasing in size when transmitted to successive generations. The function of the ataxins is not known. This locus has been mapped to chromosome 6, and it has been determined that the diseased allele contains 41-81 CAG repeats, compared to 6-39 in the normal allele, and is associated with spinocerebellar ataxia type 1 (SCA1). At least two transcript variants encoding the same protein have been found for this gene.
Synonyms
ATXN1; ataxin 1; SCA1, spinocerebellar ataxia 1 (olivopontocerebellar ataxia 1, autosomal dominant, ataxin 1); ataxin-1; ATX1; D6S504E; ATX1_HUMAN; OTTHUMP00000016065; SCA1; Spinocerebellar ataxia type 1 protein

ATXN1 Structure and Positioning

ATXN1 in humans is a protein encoded by the ATXN1 gene, which is located at 6p22.3. ATXN1 is a soluble protein with a size of 98 kDa consisting of approximately 816 amino acids. The specific size varies with the number of amino-terminated polyglutamine (polyQ). CAG repeats are highly polymorphic in the normal population. It is widely expressed in both human and mouse tissues, mainly in the nucleus in neurons and in the cytoplasm in non-neurons.

Biological Function of ATXN1

ATXN1 may play a role in certain periods of cerebellar development. In ATXN1 knockout mice (Sca1-/-), loss of ATXN1 function results in changes in short-term synaptic plasticity in the hippocampus and in some neurobehavioral abnormalities without significant neuroanatomical changes; including investigating behavior in a new setting, decreased spatial cognitive ability, activity, and athletic ability. These evidences suggest that ATXN1 plays a role in cerebellar motor function and learning and memory.

It has been shown that some proteins interact with ATXN1 and mostly interact with the carboxy-terminus containing the AXH domain. Of the known molecules that interact with ATXN1 binding, at least 16 act on the regulation of transcription and 9 act on RNA binding or metabolism. A poly(Q) amplified ATXN1 mutant will lose its ability to bind to a specific protein. In addition to its role in transcriptional regulation, ATXN1 (aa 541-767) also binds to RNA, suggesting that ATXN1 acts as an RNA-binding protein in the nucleus and cytoplasm, including regulation of RNA splicing, stability of m RNA, mRNA transport and m RNA translation.

A comparative analysis of the gene expression profile of ATXN1 knockout mice revealed that the loss of ATXN1 function leads to dysregulation of gene expression including: initiation of translation, Wnt-receptor signaling pathway, RA (retinoic acid)/thyroid hormone signaling pathways, nucleic acid binding and intracellular signaling cascades. The transcription factor HBP1 also acts through the AXH domain and related genes of the Wnt signaling pathway, and this provides new evidence that ATXN1 may also play a role in its Wnt signaling pathway through its AXH. Changes in the Wnt receptor and RA signaling pathways in ATXN1 knockout mice indicate that ATXN1 may play a role in regulating genetic information during development and in the specific differentiation of neurons.

ATXN1 and SCA1

ATXN1 is a protein of unknown function associated with spinocerebellar ataxia type 1 (SCA1). The polyQ at the amino-terminal (N-) amplification of ATXN1 led to the occurrence of SCA1. SCA1 is a delayed neurodegenerative disorder with autosomal dominant inheritance. The main clinical manifestations are the ataxia of the cerebellum, accompanied by different degrees of eye movement abnormalities, cone system and extrapyramidal peripheral neuropathy and cognitive impairment. Basic genetic alterations in SCA1 Aberrantly amplified trinucleotide CAG repeats in exon 8 of ATXN1 gene, amplified to 40-83, CAG repeats encode polyglutamine (polyQ ). PolyQ located at the amino-terminal (N-) amplification of ATXN1 resulted in the occurrence of SCA1. The more repeats the clinically the earlier the onset and the more severe the symptoms.

Although ATXN1 is widely distributed in humans, the mutated ATXN1 mainly causes degeneration of cerebellar Purkinje cells, brainstem and spinal cord neurons. ATXN1 is distributed in its cytoplasm and nuclei in the Purkinje cells of the cerebellum. It has been reported that ATXN1 has the same localization in the nucleus of the PML-oncogenic domains (POD) in the promyelocytic leukemia protein (PML) associated with the nuclear matrix. Pathological changes in SCA1 occur mainly in the Purkinje cells of the cerebellum. Mutations of ATXN1 must enter the nucleus of Purkinje cells to cause disease. The NLS at the carboxyl-terminus enables the ATXN1 protein to go from the cytoplasm to the nucleus. Mutation inactivation of the NLS region in the ATXN1 mutant with polyQ amplification will cause the original SCA1 to no longer develop. This result on the one hand shows that the function of the ATXN1 mutant is related to its localization in the nucleus. On the other hand, it also shows that the toxic effect of the amplified polyQ is mediated by its protein level, not the m RNA level.

The study found that SCA1 can be treated by inhibiting the expression of ATXN1. Keiser et al. found that after the onset of symptoms, the SCA1 phenotype can partially suppress human mutant ATXN1 mRNA by delivering rAAV (recombinant adeno-associated virus).miS1, and the symptoms are improved. The group also determined the dose of rAAV.miS1 that can be alleviated. In addition, misfolding and aggregation of the distal AXH domains in the sequence mode play an important role in the expansion of the polyglutamine fragment. De et al. found that the dimeric interface of AXH is replaced by a new interaction by resolving the structure of the complex of AXH with the peptide from the interacting transcriptional repressor CIC. When blocked by CIC peptides, AXH aggregation and misfolding are impaired, and based on this, drugs for the treatment of SCA1 can be designed.

Figure 1. Figure 1. Solution structure of the ATX1 AXH/L-CICp complex. (De, et al. 2013). (Steinestel, et al. 2014).

ATXN1 and Tumor

ATXN1 is a component of the Notch signaling pathway that mediates hypoxia-supply (hypoxia)-induced tumor cell migration and invasion, an important feature of solid tumors. Hypoxia is an independent predictor of poor prognosis in patients with cervical cancer and other types of cancer; in particular, hypoxia can enhance tumor invasiveness, metastasis, and chemoresistance. The initial step in the process of tumor cell metastasis involves epithelial-mesenchymal transition (EMT). Kang et al. reported that overexpression of ATXN1 enhanced the expression of E-cadherin (E-cadherin) in protein and mRNA levels in MCF-7 breast cancer cells. Subsequently, the group found a novel mechanism of ATXN1 regulating epithelial-to-mesenchymal transition (EMT) in cancer cells: through the ubiquitination and degradation associated with MDM2, the up-regulation of Notch-induced intracellular domain of Notch decreased the expression of ATXN1. In cervical cancer cells, ATXN1 knockdown induces EMT by directly regulating Snail expression, leading to activation of matrix metalloproteinases and promoting cell migration and invasion. These findings provide insights into a new mechanism of tumorigenesis and will promote the development of new and more effective treatments for cancer.

Reference:

  1. Kang A R, An H T, Ko J, et al. Ataxin-1 regulates epithelial-mesenchymal transition of cervical cancer cells. Oncotarget, 2017, 8(11):18248-18259.
  2. Keiser M S, Monteys A M, Corbau R, et al. RNAi prevents and reverses phenotypes induced by mutant human ataxin-1. Annals of Neurology, 2016, 80(5):754-765.
  3. Deriu M A, Grasso G, Tuszynski J A, et al. Characterization of the AXH domain of ataxin-1 using enhanced sampling and functional mode analysis. Proteins Structure Function & Bioinformatics, 2016, 84(5):666-673.
  4. De C C, Menon R P, Kelly G, et al. Protein-protein interactions as a strategy towards protein-specific drug design: the example of ataxin-1. Plos One, 2013, 8(10):e76456.
  5. Dechiara C, Rees M, Menon R, et al. Self-Assembly and Conformational Heterogeneity of the AXH Domain ofAtaxin-1: An Unusual Example of a Chameleon Fold. Biophysical Journal, 2013, 104(6):1304.