Research Interests:
Our research group uses genetic, behavioral and cell biological approaches to explore the pathogenesis and treatment of polyglutamine neurodegenerative diseases.
Several dominantly inherited spinocerebellar ataxias (SCAs) are caused by expansion of a CAG repeat that encodes glutamine. We discovered that ataxin-1 (ATXN1) with an expanded glutamine tract accumulates in neurons of patients and mouse models. Our works showed that toxicity of mutant ATXN1 is due to soluble protein and its interacting proteins. Thus, polyglutamine-expanded mutant ATXN1 is able to interact with several other nuclear proteins and incorporate into native complexes similar to wild type protein. ATXN1 interacts with several proteins many of which are transcriptional regulators such as Gfi-1, ROR ± , and Capicua, and somehow interferes with their function in vivo (Tsuda, 2005; Lam, 2006; Sierra, 2006). Importantly, we found that mutant ATXN1 must be in its large native complex to cause neurodegeneration (Lam, 2007). We identified partners of ATXN1 that interact with it in a manner dependent on two criteria necessary for toxicity: polyglutamine expansion and phosphorylation at serine 776. Polyglutamine expansion as well as phosphorylation of serine 776 in ATXN1 favors the formation of a particular protein complex containing a putative regulator of RNA splicing RBM17. We further found that changing the serine at position 776 to an aspartic acid (a substitution that can mimic phosphorylation) renders a wild type allele of ataxin-1 with 30 glutamines pathogenic in vivo. Mice expressing ataxin-1 30Q-D776 have a phenotype very similar to that seen in mice expressing ataxin-1 82Q-S776. These findings demonstrate the glutamine expansion in ATXN1 enhance protein/protein interactions that are normally regulated by its phosphorylation at serine at position 776 and that polyglutamine-induced misregulation of S776 phosphorylation and subsequent alterations in nuclear trafficking underlie SCA1 pathogenesis.
Selected Publications:
(For a comprehensive list of recent publications, refer to PubMed, a service provided by the National Library of Medicine.)
Lim, J., Crespo-Barreto, J., Jafar-Nejad, P., Bowman, A.B., Richman, R., Hill, D.E., Orr, H.T. and Zoghbi, H.Y. (2008) Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1, Nature 452: 713-719.
Jorgensen ND, Andresen JM, Pitt JE, Swenson MA, Zoghbi HY, Orr HT. Hsp70/Hsc70 regulates the effect phosphorylation has on stabilizing ataxin-1. J Neurochem. 2007 Sep;102(6):2040-8.
Swanson MS, Orr HT. Fragile X tremor/ataxia syndrome: blame the messenger! Neuron. 2007 Aug 16;55(4):535-7.
Watase K, Gatchel JR, Sun Y, Emamian E, Atkinson R, Richman R, Mizusawa H, Orr HT, Shaw C, Zoghbi HY. Lithium therapy improves neurological function and hippocampal dendritic arborization in a spinocerebellar ataxia type 1 mouse model. PLoS Med. 2007 May;4(5):e182.
Bowman AB, Lam YC, Jafar-Nejad P, Chen HK, Richman R, Samaco RC, Fryer JD, Kahle JJ, Orr HT, Zoghbi HY. Duplication of Atxn1l suppresses SCA1 neuropathology by decreasing incorporation of polyglutamine-expanded ataxin-1 into native complexes. Nat Genet. 2007 Mar;39(3):373-9.
Orr HT, Zoghbi HY. Trinucleotide repeat disorders. Annu Rev Neurosci. 2007;30:575-621. Review.
Lam YC, Bowman AB, Jafar-Nejad P, Lim J, Richman R, Fryer JD, Hyun ED, Duvick LA, Orr HT, Botas J, Zoghbi HY. ATAXIN-1 interacts with the repressor Capicua in its native complex to cause SCA1 neuropathology. Cell. 2006 Dec 29;127(7):1335-47.
Serra HG, Duvick L, Zu T, Carlson K, Stevens S, Jorgensen N, Lysholm A, Burright E, Zoghbi HY, Clark HB, Andresen JM, Orr HT. RORalpha-mediated Purkinje cell development determines disease severity in adult SCA1 mice. Cell. 2006 Nov 17;127(4):697-708.
He Y, Zu T, Benzow KA, Orr HT, Clark HB, Koob MD. Targeted deletion of a single Sca8 ataxia locus allele in mice causes abnormal gait, progressive loss of motor coordination, and Purkinje cell dendritic deficits. J Neurosci. 2006 Sep 27;26(39):9975-82.
Riley BE, Orr HT. Polyglutamine neurodegenerative diseases and regulation of transcription: assembling the puzzle. Genes Dev. 2006 Aug 15;20(16):2183-92.
Ellerby LM, Orr HT. Neurodegenerative disease: cut to the chase. Nature. 2006 Aug 10;442(7103):641-2.
Current Graduate Students:
Justin Barnes (Neuroscience, University of Minnesota).
Former Graduate Students:
Nathan Jorgensen (Ph.D. 2007,
Neuroscience, University of Minnesota). |
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