Modulating Calcium Signaling Pathways in Cerebellar Purkinje Cells Alleviates Spinocerebellar Ataxia 2
| dc.contributor.advisor | Bezprozvanny, Ilya | en |
| dc.creator | Kasumu, Adebimpe Wakila | en |
| dc.date.accessioned | 2012-07-16T17:59:08Z | |
| dc.date.available | 2012-07-16T17:59:08Z | |
| dc.date.issued | 2012-07-16 | |
| dc.description.abstract | Spinocerebellar ataxia 2 (SCA2) is a neurodegenerative disorder characterized by progressive ataxia. SCA2 results from the polyglutamine expansion in the cytosolic protein ataxin-2 (Atx2). Cerebellar Purkinje cells (PC) are primarily affected in SCA2, but the cause of PC dysfunction, PC death and motor incoordination in SCA2 is poorly understood. It has been reported that mutant, but not wild type Atx2, specifically binds to the inositol 1,4,5-trisphosphate receptor (InsP3R) and increases its sensitivity to activation by IP3. Thus, this toxic gain-of-function of Atx2 results in supranormal calcium (Ca2+) release from the PC endoplasmic reticulum and may play a key role in the development of SCA2 pathology. The primary focus of this dissertation will be to further elucidate the underlying mechanism of SCA2 pathogenesis, identify therapeutic targets and develop a potential treatment of SCA2. The first part of this dissertation will test the hypothesis that suppressing InsP3R-mediated Ca2+ signaling alleviates age-dependent dysfunction, and degeneration of PCs in SCA2 mice. The second part of this dissertation will focus on testing the efficacy of novel compounds that modulate calcium-activated potassium (SK) channels in the symptomatic treatment of SCA2. I conclude from this work that supranormal InsP3--Ca2+ signaling plays an important role in SCA2 pathogenesis. Partial inhibition of InsP3-mediated Ca2+ signaling or regularizing PC firing with SK channel modulators could provide therapeutic benefit for the patients afflicted with SCA2 and possibly other SCAs. | en |
| dc.identifier.oclc | 812424059 | |
| dc.identifier.uri | https://hdl.handle.net/2152.5/999 | |
| dc.language.iso | en | en |
| dc.subject | Purkinje Cells | en |
| dc.subject | Calcium Channels | en |
| dc.subject | Spinocerebellar Ataxias | en |
| dc.title | Modulating Calcium Signaling Pathways in Cerebellar Purkinje Cells Alleviates Spinocerebellar Ataxia 2 | en |
| dc.type | Thesis | en |
| dc.type.material | Text | en |
| thesis.date.available | 2014-07-06 | |
| thesis.degree.department | Graduate School of Biomedical Sciences | en |
| thesis.degree.discipline | Neuroscience | en |
| thesis.degree.grantor | UT Southwestern Medical Center | en |
| thesis.degree.level | Doctoral | en |
| thesis.degree.name | Doctor of Philosophy | en |