Our lab seeks to understand the biology of spinocerebellar ataxia type 1 (SCA1), a neurodegenerative disease that belongs to the family of disorders caused by the expansion of a polyglutamine (polyQ) tract in the disease protein. In SCA1 the polyglutamine repeat expansion occurs in the protein ataxin-1. Previous studies have established that the expanded polyQ tract alters ataxin-1's conformation, clearance, and ability to form complexes with native partner proteins. Within the first two weeks of life, however, long before behavioral or degenerative pathology is apparent, mutant ataxin-1 disrupts the transcription of specific genes. Although it is still unclear how this happens, we have uncovered one likely mechanism: we have found that cerebella of SCA1 mice exhibit hypoacetylation of histones, particularly at the promoters of down-regulated genes. This post-translational modification of histones is correlated with transcriptional repression. It is intriguing that We hypothesize that mutant ataxin-1 causes transcriptional repression by recruiting these corepressors to cause pathologic repression of target genes. Our preliminary findings support this hypothesis and suggest that genetically depleting one of these corepressors (LANP) improves both the ataxic phenotype and the neuropathology of SCA1 knock-in mice. To better understand the role of these corepressors in SCA1 pathogenesis we propose the following aims: (1) Characterize Sca1154Q/2Q mice lacking LANP with a range of behavioral, motor, and neuropathological assays to delineate the facets of the SCA1 phenotype improved by loss of LANP;(2) Elucidate the contribution of the histone deacetylase HDAC3 to Purkinje cell function and SCA1 pathology;and (3) Identify the direct targets of ataxin-1 repression and mechanistically probe how ataxin-1 modulates gene expression.
Spinocerebellar Ataxia Type 1 (SCA1) is an adult onset neurodegenerative disease characterized by deterioration of the cerebellum and the brainstem. In this proposal we seek to elucidate mechanisms underlying changes in gene expression, a hallmark of SCA1. The ultimate goal is to use these insights to develop rational therapies to treat patients suffering from this relentless and incurable genetic disease.
|Lowery, Jason; Jain, Nikhil; Kuczmarski, Edward R et al. (2016) Abnormal intermediate filament organization alters mitochondrial motility in giant axonal neuropathy fibroblasts. Mol Biol Cell 27:608-16|
|Lin, Ni-Hsuan; Huang, Yu-Shan; Opal, Puneet et al. (2016) The role of gigaxonin in the degradation of the glial-specific intermediate filament protein GFAP. Mol Biol Cell 27:3980-3990|
|Cvetanovic, M; Ingram, M; Orr, H et al. (2015) Early activation of microglia and astrocytes in mouse models of spinocerebellar ataxia type 1. Neuroscience 289:289-99|
|Venkatraman, Anand; Hu, Yuan-Shih; Didonna, Alessandro et al. (2014) The histone deacetylase HDAC3 is essential for Purkinje cell function, potentially complicating the use of HDAC inhibitors in SCA1. Hum Mol Genet 23:3733-45|
|Mahammad, Saleemulla; Murthy, S N Prasanna; Didonna, Alessandro et al. (2013) Giant axonal neuropathy-associated gigaxonin mutations impair intermediate filament protein degradation. J Clin Invest 123:1964-75|
|Cvetanovic, Marija; Kular, Rupinder K; Opal, Puneet (2012) LANP mediates neuritic pathology in Spinocerebellar ataxia type 1. Neurobiol Dis 48:526-32|
|Cvetanovic, Marija; Patel, Jay M; Marti, Hugo H et al. (2011) Vascular endothelial growth factor ameliorates the ataxic phenotype in a mouse model of spinocerebellar ataxia type 1. Nat Med 17:1445-7|
|Kular, Rupinder K; Gogliotti, Rocky G; Opal, Puneet (2010) Cpd-1 null mice display a subtle neurological phenotype. PLoS One 5:|