https://med.umn.edu/bio/lab-med-and-pathology-faculty/harry-orr
Dr. Orr’s lab is focused on the molecular genetics of neurodegenerative diseases, principally the autosomal dominant form of spinocerebellar ataxia (SCA1).
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. Orr and his colleagues also 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, and are working with a company that has developed anti-sense oligonucleotide chemistry. 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.
