An Investigation on Molecular Mechanisms Underlying Mutant Ataxin-3- and Ataxin-7-Induced Neuronal Dysfunction and Death SMN

Spinocerebellar ataxia type 3 (SCA3) or Machado-Joseph disease is an inherited autosomal dominant neurodegenerative disorder caused by abnormal expansion of CAG repeats coding for polyglutamine tract within a protein called ataxin-3.Wild-type ataxin-3 is believed to function as an ubiquitin protease and a transcriptional repressor. In contrast to wide distribution of ataxin-3 in the brain, SCA3 neurodegeneration is mainly found in the pontine nucleus, substantia nigra, cerebellum and spinal cord. Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurological disorder and caused by CAG trinucleotide repeat expansion within the coding region of SCA7 gene. Ataxin-7, SCA7 gene product, is an integral component of the mammalian TFTC/STAGA transcription coactivator complexes and believed to regulate transcriptional activity in the brain. Despite the wide distribution of ataxin-7 in the brain, SCA7 neurodegeneration is mainly found in the cerebellum, inferior olive and spinal cord. SCA3 is the most common subtype of spinocerebellar ataxias, and SCA7 is one of the most prevalent subtypes of spinocerebellar ataxias. Both SCA3 and SCA7 belong to the family of polyglutamine neurodegenerative disorders resulting from an expansion of unstable CAG repeat within the coding region of gene. Because all of polyglutamine diseases result from the same genetic mutation, it has been hypothesized that common pathogenic mechanisms are involved in the pathogenesis of these neurological disorders. Consistent with this hypothesis, our in vitro and in vivo studies demonstrated that both polyglutamine-expanded ataxin-3-Q79 and ataxin-7-Q75 upregulate pro-apoptotic Bax and downregulate anti-apoptotic Bcl-xL expression, which leads to the activation of mitochondrial apoptotic pathway and resulting apoptotic neuronal death. Microarray analysis using SCA3 or SCA7 transgenic mice suggests that both mutant ataxin-3-Q79 and ataxin-7-Q75 cause cerebellar neurotoxicity and dysfunction by downregulating mRNA expressions of proteins involved in synaptic transmission, signal transduction, myelin formation, neuronal survival or neuronal differentiation and heat shock proteins. Therefore, apoptotic neuronal death, caused by upregulated Bax expression and downregulated Bcl-xL expression, and cerebellar dysfunction, caused by downregulated expressions of genes involved in synaptic and cellular functions of cerebellar neurons, are two common pathogenic mechanisms of SCA3 and SCA7. Further studies are required to investigate the exact molecular mechanisms by which mutant ataxin-3-Q79 or ataxin-7-Q75 causes transcriptional downregulation and alters the expression of Bax and Bcl-xL. In order to elucidate molecular mechanisms underlying mutant ataxin-3- and ataxin-7-induced neuronal dysfunction and death in affected brain regions, we will perform the following investigations using SCA3 or SCA7 transgenic mouse model and ataxin-3- or ataxin-7-deficient mice: (1) We will test the hypothesis that mutant ataxin-3-Q79 or ataxin-7-Q75 downregulates Bcl-xL expression by impairing NF-􀁎B activity and upregulates Bax expression by enhancing p53 transcriptional activity. (2)We will provide the direct evidence that mutant ataxin-3-Q79- or ataxin-7-Q75-induced transcriptional dysregulation results in impaired cellular and synaptic functions of cerebellar neurons. (3)We will test the hypothesis 2 that mutant ataxin-3-Q79 or ataxin-7-Q75 causes cerebellar transcriptional downregulation by sequestering transcription factors/co-factors or inducing histone hypo-acetylation. (4) Ataxin-3 or ataxin-7 knockout mice are prepared to test the hypothesis that polyglutamine expansion-induced partial loss-of-function of wild-type ataxin-3 or ataxin-7 is involved in the pathogenesis of SCA3 or SCA7. The results obtained from the present investigation should shed light on pathogenic mechanisms of SCA3 and SCA7 and physiological functions of ataxin-3 and ataxin-7. Better understanding of molecular pathogenesis of SCA3 and SCA7 could lead to the development of possible therapeutic strategies for SCA3, SCA7 and other polyglutamine neurological disorders.

Project ID:PC9712-0482
External Project ID:NSC97-2321-B182-006