Harry Orr, PhD

Dr. Orr is professor and the James Schindler and Bob Allison Ataxia Chair in Translational Research in the department, directs the Institute of Translational Neuroscience, and is a member of the Division of Molecular Pathology and Genomics.  His research is focused on the molecular genetics of neurodegenerative diseases, principally the autosomal dominant form of spinocerebellar ataxia (SCA1). Patients usually develop SCA1 in mid-life. They experience loss of motor coordination and develop slurred speech, spasticity, and cognitive impairment. These symptoms arise from the loss of Purkinje cells and damage to other nerve cells in the brain's cerebellar cortex. Orr and his colleagues cloned the SCA1 gene and found that the disease is caused by the expansion of an unstable, repeated cytosine-adenine-guanine (CAG) sequence in DNA. The length of the trinucleotide repeat is associated with when symptoms develop.The trinucleotide repeat encodes an expanded polyglutamine tract, an important step in disease pathogenesis. Orr and his colleagues established the first transgenic mouse model for SCA1 with which they were able to induce ataxia with Purkinje cell features characteristic of SCA1 by inserting CAG repeats. The model has helped his team understand how the SCA1 mutant polyglutamine protein, ataxin-1, moves from the cytoplasm into the nucleus of Purkinje cells where together with other protein complexes it causes Purkinje dendrites to atrophy. They found that phosphorylation of a specific ataxin-1 serine results in greater stabilization of the mutant protein, which alters the normal ratio of stabilized versus degraded protein and results in aberrant binding and disease.In the experimental therapeutics arena, Orr and colleagues are using RNA interference (RNAi) and adeno-associated virus (AAV) vectors as a delivery system to reduce ataxin-1 expression in Purkinje cells. Orr also working with a company that has developed anti-sense oligonucleotide chemistry. Anti-sense oligonucleotides act at the level of messenger RNA before proteins are produced. Delivering drugs to the central nervous system is difficult. Delivering molecular therapies to the deep cerebellar nuclei of the cerebellar cortex, where Purkinje neurons cluster and terminate, is a significant challenge. Orr's University colleagues have experience using AAV vectors to deliver genes to Purkinje cells. When human trials begin, the hope is that a sufficient number of therapeutic molecules will be taken in by Purkinje cell terminals and transferred to the cell bodies to be beneficial to patients.

Publications

• Duvick L, Southern WM, Benzow KA, Burch ZN, Handler HP, Mitchell JS, Kuivinen H, Gadiparthi U, Yang P, Soles A, Sheeler CA, Rainwater O, Serres S, Lind EB, Nichols-Meade T, You Y, O'Callaghan B, Zoghbi HY, Cvetanovic M, Wheeler VC, Ervasti JM, Koob MD, Orr HT. Mapping SCA1 regional vulnerabilities reveals neural and skeletal muscle contributions to disease. JCI Insight. 2024 Mar 21;9(9):e176057. doi: 10.1172/jci.insight.176057.
• Liu CJ, Williams KE, Orr HT, Akkin T. Visualizing and mapping the cerebellum with serial optical coherence scanner. Neurophotonics. 2017 Jan;4(1):011006.
• Rubinsztein DC, Orr HT. Diminishing return for mechanistic therapeutics with neurodegenerative disease duration?: There may be a point in the course of a neurodegenerative condition where therapeutics targeting disease-causing mechanisms are futile. Bioessays. 2016 Oct;38(10):977-80. doi: 10.1002/bies.201600048.
• Ingram M, Wozniak EA, Duvick L, Yang R, Bergmann P, Carson R, O'Callaghan B, Zoghbi HY, Henzler C, Orr HT. Cerebellar Transcriptome Profiles of ATXN1 Transgenic Mice Reveal SCA1 Disease Progression and Protection Pathways. Neuron. 2016 Mar 16;89(6):1194-207. doi: 10.1016/j.neuron.2016.02.011.
• Malhotra D, Linehan JL, Dileepan T, Lee YJ, Purtha WE, Lu JV, Nelson RW, Fife BT, Orr HT, Anderson MS, Hogquist KA, Jenkins MK.
  Tolerance is established in polyclonal CD4(+) T cells by distinct mechanisms, according to self-peptide expression patterns.
  Nat Immunol. 2016 Feb;17(2):187-95. doi: 10.1038/ni.3327.