REGULATION OF THE SOLUBILITY AND SUBCELLULAR LOCALIZATION OF POLYGLUTAMINE PROTEINS

The polyglutamine expansion diseases include spinobular muscular atrophy (SBMA), Huntington's disease (HD), dentatorubro-pallidoluysioanatrophy (DRPLA), and several spinocerebellar ataxias (SCAs). Remarkably, each is caused by CAG codon expansion within a particular gene that produces polyglutamine tract enlargement in the protein. Each such mutant protein causes selective neurodegeneration within the CNS. Formation of nuclear and cytoplasmic aggregates that include such mutant proteins is a characteristic feature of polyglutamine expansion diseases in patients as well as transgenic animal and cell culture models. The precise role of these protein aggregates in pathogenesis remains uncertain.

UCSF researhers have discovered that a cell pathway that is regulated by a particular hormone receptor can selectively modify aggregation and subcellular localization of expanded polyglutamine proteins - in two distinct cell lines with two different expanded polyglutamine proteins. Although the cellular mechanism is unknown, it appears to be due to activation of specific gene expression. Work is underway to identify the gene(s) that mediate the receptor's regulation of nuclear transport and to test hormone effects in mice that are transgenic for polyglutamine expansion proteins. This work may have implications for our understanding of nuclear trafficking, disorders of other misfolded proteins, and this specific receptor's regulation of gene expression, in addition to bringing us closer to a cure for a devastating group of neurodegenerative diseases.

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Joel B. Kirschbaum, Ph.D.
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(415) 353-4462 phone
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Joel Kirschbaum, Ph.D.

Reference: OTM Case #SF2000-006