Research Interests:
Our group works at unraveling genes that encode proteins critical
for proper neuronal function. The primary approach is to study genes
that have a role in neurodegeneration. We study the molecular basis
of spinocerebellar ataxia type 1 (SCA1). SCA1 is a dominantly inherited
neurodegenerative disease caused by an expanded glutamine tract in
ataxin-1. How does a mutant glutamine tract in ataxin-1 lead to neuronal
dysfunction and cell loss? To answer this, we feel it is important
to understand the normal function of ataxin-1 and how a mutant polyglutamine
tract alters its function. Using transgenic mice, we found that mutant
ataxin-1 must enter the nucleus in affected neurons to cause disease
(Klement, 1998). Several strategies have been used to show that in
the presence of mutant ataxin-1 gene expression by Purkinje cells
is altered (Serra, 2004). What's more, ataxin-1 has RNA-binding activity
(Yue, 2001), and is able to shuttle between the nucleus and cytoplasm.
We found that ataxin-1 is normally phosphorylated at serine 776 (S776)
that is critical for ataxin-1 induced degeneration (Emamian, 2003).
Recently, we generated a conditional mouse model of SCA1 in which
the expression of mutant ataxin-1 can be turned on and off at will
(Zu, 2004). These mice are proving to be a valuable resource for examining
the process of disease as well as pathways that are important for
neuronal repair.
Selected Publications:
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). |
Return
to: U of M Home
