Ataxin 3 Explained

Ataxin-3 is a protein that in humans is encoded by the ATXN3 gene.^{[1] [2]}

Clinical significance

Machado–Joseph disease, also known as spinocerebellar ataxia-3, is an autosomal dominant neurologic disorder. The protein encoded by the ATXN3 gene contains CAG repeats in the coding region, and the expansion of these repeats from the normal 13-36 to 68-79 is the cause of Machado–Joseph disease. This disorder is thus a trinucleotide repeat disorder type I known as a polyglutamine (PolyQ) disease. There is an inverse correlation between the age of onset and CAG repeat numbers. Alternatively spliced transcript variants encoding different isoforms have been described for this gene.

Interactions

Ataxin 3 has been shown to interact with:

• RAD23A,^[3]
• RAD23B,^[3] and
• VCP.^{[4] [5]}

Further reading

• Goto J, Watanabe M, Ichikawa Y, Yee SB, Ihara N, Endo K, Igarashi S, Takiyama Y, Gaspar C, Maciel P, Tsuji S, Rouleau GA, Kanazawa I . Machado-Joseph disease gene products carrying different carboxyl termini . Neuroscience Research . 28 . 4 . 373–7 . Aug 1997 . 9274833 . 10.1016/S0168-0102(97)00056-4 . 27241785 .
• Schöls L, Vieira-Saecker AM, Schöls S, Przuntek H, Epplen JT, Riess O . Trinucleotide expansion within the MJD1 gene presents clinically as spinocerebellar ataxia and occurs most frequently in German SCA patients . Human Molecular Genetics . 4 . 6 . 1001–5 . Jun 1995 . 7655453 . 10.1093/hmg/4.6.1001 .
• Stevanin G, Cancel G, Dürr A, Chneiweiss H, Dubourg O, Weissenbach J, Cann HM, Agid Y, Brice A . The gene for spinal cerebellar ataxia 3 (SCA3) is located in a region of approximately 3 cM on chromosome 14q24.3-q32.2 . American Journal of Human Genetics . 56 . 1 . 193–201 . Jan 1995 . 7825578 . 1801316 .
• Kawaguchi Y, Okamoto T, Taniwaki M, Aizawa M, Inoue M, Katayama S, Kawakami H, Nakamura S, Nishimura M, Akiguchi I . CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1 . Nature Genetics . 8 . 3 . 221–8 . Nov 1994 . 7874163 . 10.1038/ng1194-221 . 29188685 .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . Jan 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Ikeda H, Yamaguchi M, Sugai S, Aze Y, Narumiya S, Kakizuka A . Expanded polyglutamine in the Machado-Joseph disease protein induces cell death in vitro and in vivo . Nature Genetics . 13 . 2 . 196–202 . Jun 1996 . 8640226 . 10.1038/ng0696-196 . 21966287 .
• Paulson HL, Das SS, Crino PB, Perez MK, Patel SC, Gotsdiner D, Fischbeck KH, Pittman RN . Machado-Joseph disease gene product is a cytoplasmic protein widely expressed in brain . Annals of Neurology . 41 . 4 . 453–62 . Apr 1997 . 9124802 . 10.1002/ana.410410408 . 43460483 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . Oct 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Wellington CL, Ellerby LM, Hackam AS, Margolis RL, Trifiro MA, Singaraja R, McCutcheon K, Salvesen GS, Propp SS, Bromm M, Rowland KJ, Zhang T, Rasper D, Roy S, Thornberry N, Pinsky L, Kakizuka A, Ross CA, Nicholson DW, Bredesen DE, Hayden MR . Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract . The Journal of Biological Chemistry . 273 . 15 . 9158–67 . Apr 1998 . 9535906 . 10.1074/jbc.273.15.9158 . free .
• Tait D, Riccio M, Sittler A, Scherzinger E, Santi S, Ognibene A, Maraldi NM, Lehrach H, Wanker EE . Ataxin-3 is transported into the nucleus and associates with the nuclear matrix . Human Molecular Genetics . 7 . 6 . 991–7 . Jun 1998 . 9580663 . 10.1093/hmg/7.6.991 . free . 10.1.1.588.3970 .
• Wang G, Sawai N, Kotliarova S, Kanazawa I, Nukina N . Ataxin-3, the MJD1 gene product, interacts with the two human homologs of yeast DNA repair protein RAD23, HHR23A and HHR23B . Human Molecular Genetics . 9 . 12 . 1795–803 . Jul 2000 . 10915768 . 10.1093/hmg/9.12.1795 .
• Ichikawa Y, Goto J, Hattori M, Toyoda A, Ishii K, Jeong SY, Hashida H, Masuda N, Ogata K, Kasai F, Hirai M, Maciel P, Rouleau GA, Sakaki Y, Kanazawa I . The genomic structure and expression of MJD, the Machado-Joseph disease gene . Journal of Human Genetics . 46 . 7 . 413–22 . 2001 . 11450850 . 10.1007/s100380170060 . free .
• Chai Y, Shao J, Miller VM, Williams A, Paulson HL . Live-cell imaging reveals divergent intracellular dynamics of polyglutamine disease proteins and supports a sequestration model of pathogenesis . Proceedings of the National Academy of Sciences of the United States of America . 99 . 14 . 9310–5 . Jul 2002 . 12084819 . 123137 . 10.1073/pnas.152101299 . 2002PNAS...99.9310C . free .
• Yoshida H, Yoshizawa T, Shibasaki F, Shoji S, Kanazawa I . Chemical chaperones reduce aggregate formation and cell death caused by the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretch . Neurobiology of Disease . 10 . 2 . 88–99 . Jul 2002 . 12127147 . 10.1006/nbdi.2002.0502 . 25183307 . free .
• Li F, Macfarlan T, Pittman RN, Chakravarti D . Ataxin-3 is a histone-binding protein with two independent transcriptional corepressor activities . The Journal of Biological Chemistry . 277 . 47 . 45004–12 . Nov 2002 . 12297501 . 10.1074/jbc.M205259200 . free .
• Albrecht M, Hoffmann D, Evert BO, Schmitt I, Wüllner U, Lengauer T . Structural modeling of ataxin-3 reveals distant homology to adaptins . Proteins . 50 . 2 . 355–70 . Feb 2003 . 12486728 . 10.1002/prot.10280 . 25660172 .
• Marchal S, Shehi E, Harricane MC, Fusi P, Heitz F, Tortora P, Lange R . Structural instability and fibrillar aggregation of non-expanded human ataxin-3 revealed under high pressure and temperature . The Journal of Biological Chemistry . 278 . 34 . 31554–63 . Aug 2003 . 12766160 . 10.1074/jbc.M304205200 . free .

External links

• GeneReviews/NCBI/NIH/UW entry on Spinocerebellar Ataxia Type 3

Notes and References

1. Takiyama Y, Nishizawa M, Tanaka H, Kawashima S, Sakamoto H, Karube Y, Shimazaki H, Soutome M, Endo K, Ohta S . The gene for Machado-Joseph disease maps to human chromosome 14q . Nature Genetics . 4 . 3 . 300–4 . Jul 1993 . 8358439 . 10.1038/ng0793-300 . 27424416 .
2. Web site: Entrez Gene: ATXN3 ataxin 3.
3. Wang G, Sawai N, Kotliarova S, Kanazawa I, Nukina N . Ataxin-3, the MJD1 gene product, interacts with the two human homologs of yeast DNA repair protein RAD23, HHR23A and HHR23B . Human Molecular Genetics . 9 . 12 . 1795–803 . Jul 2000 . 10915768 . 10.1093/hmg/9.12.1795 .
4. Doss-Pepe EW, Stenroos ES, Johnson WG, Madura K . Ataxin-3 interactions with rad23 and valosin-containing protein and its associations with ubiquitin chains and the proteasome are consistent with a role in ubiquitin-mediated proteolysis . Molecular and Cellular Biology . 23 . 18 . 6469–83 . Sep 2003 . 12944474 . 193705 . 10.1128/MCB.23.18.6469-6483.2003 .
5. Wang Q, Li L, Ye Y . Inhibition of p97-dependent protein degradation by Eeyarestatin I . The Journal of Biological Chemistry . 283 . 12 . 7445–54 . Mar 2008 . 18199748 . 2276333 . 10.1074/jbc.M708347200 . free .