Isolation of the spinal muscular atrophy candidate gene: The neuronal apoptosis inhibitor protein.
|Title:||Isolation of the spinal muscular atrophy candidate gene: The neuronal apoptosis inhibitor protein.|
|Abstract:||The childhood spinal muscular atrophies (SMA) are neurodegenerative disorders characterised by progressive spinal cord motor neuron depletion and are among the most common autosomal recessive disorders. Type I SMA is the most frequent monogenic cause of death in infancy. The loss of motor neurons in SMA, has led to suggestions that an inappropriate continuation or reactivation of normally occurring motor neuron apoptosis may underlie the disorder. The gene resonsible for the SMA's was mapped to a region of 5q13 Banked proximally by the marker CMS-1 and distally by the marker D5S557. In keeping with the hypothesis that a mechanism of apoptosis may underlie the disorder, we have isolated a gene encoding the neuronal apoptosis inhibitor protein (NAIP), which is homologous to baculoviral inhibitor of apoptosis proteins (IAP) and is partially deleted in individuals with Type I SMA. Concurrently, a second candidate gene encoding survival motor neuron (SMN), which is contiguous with the NAIP locus on 5q13.1 was also reported (Levebre et al., 1995. Cell 80, 155). SMN is deleted in a significant majority of SMA individuals, leaving unclear the precise role of the two genes in SMA causation. In an effort to delineate the role of NAIP in SMA pathogenesis, we have studied the effect of NAIP on cell death induced by different apoptotic triggers and determined the cellular distribution of the protein in human spinal cord. We report that overexpression of NAIP in Rat-1, HeLa and CHO cells suppresses apoptosis induced by menadione, tumor necrosis factor alpha (TNF-$\alpha$) and serum withdrawal. Immunocytochemistry employing polyclonal antiserum raised against human NAIP demonstrates immunoreactivity in motor neurons. NAIP mediated inhibition of cell death and the immunolocalization of the protein to motor neurons are consistent with a role for NAIP both in the naturally occurring programmed motor neuron death. and when defective, in the pathogenesis of SMA. Moreover, NAIP appears to be the first member of a novel family of human genes with anti-apoptotic activity. Three novel human IAPs have subsequently been identified and shown to suppress apoptosis (Liston et al. 1996. Nature 379, 349). Two of these were also identified based on their ability to associate with the tumor necrosis factor receptor II (TNFRII) via a TNF receptor associated factor 1 and 2 (TRAF1-TRAF2) heterocomplex (Rothe et al., 1995. Cell 83, 1243) These data provide evidence for a central role of NAIP and IAPs not only in apoptosis but as regulators in these signalling pathways. (Abstract shortened by UMI.)|
|Collection||Thèses, 1910 - 2010 // Theses, 1910 - 2010|