Spinal and bulbar muscular atrophy (SBMA) is one of eight inherited neurodegenerative diseases known to be caused by CAG repeat expansion. The expansion results in an expanded polyglutamine tract, which likely confers a novel, toxic function the affected protein. Cell culture transgenic mouse studies have implicated nucleus as site for pathogenesis, suggesting that critical nuclear factor or process disrupted In this report we present evidence CREB-binding protein (CBP), transcriptional...

ABSTRACT Cell death is a common feature of neural development in all vertebrates. The bcl-2 proto-oncogene has been shown to protect variety cell types from programmed death. We have examined the distribution protein developing and adult nervous systems. widespread during embryonic development. Proliferating neuroepithelial cells ventricular zones as well postmitotic cortical plate, cerebellum, hippocampus spinal cord express bcl-2. Postnatally, principally retained granule cerebellum...

A clone that cross-hybridizes with a mouse p53 probe has been isolated from cDNA library of simian virus 40-transformed human fibroblasts. This cloned was used as to examine DNAs obtained human-rodent somatic cell hybrids have segregated chromosomes. The results show the gene is located on chromosome 17. In addition, Southern analysis prepared cells containing 17 translocation allowed regional localization most distal band short arm this (17p13). Localization 17p13 confirmed by in situ...

Abstract Spinal and bulbar muscular atrophy (SBMA) is an X‐linked motor neuronopathy caused by the expansion of unstable CAG repeat in coding region androgen receptor (AR) gene. To study AR protein expression normal SBMA individuals, we used several antibodies that recognize protein, analyzed neural nonneural tissues immunohistochemistry western blotting. Both mutant proteins were widely distributed, predominantly, but not exclusively, cytoplasm neurons regardless pathological involvement,...

Recent evidence indicates that transcriptional abnormalities may play an important role in the pathophysiology of polyglutamine diseases. In present study, we have explored extent to which polyglutamine-related changes gene expression be independent protein context by comparing mouse models dentatorubral–pallidoluysian atrophy (DRPLA) and Huntington's disease (HD). Microarray profiling was conducted mice same background strain promoter employed direct full-length atrophin-1 or partial...

Transgenic models of neurodegenerative disease have proved uniquely powerful for delineating pathways neuronal dysfunction and cell death. We developed a transgenic model the polyglutamine spinal bulbar muscular atrophy (SBMA), an adult-onset, slowly progressive motor neuron caused by expansion in androgen receptor (AR). Mice bearing human AR with 112 glutamines reproduce many aspects SBMA, including progressive, gender-specific deficits, intranuclear inclusions. Despite substantial deficits...

Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by the expansion of polyglutamine repeat within androgen receptor (AR). We have studied mutant AR in an vitro system, find both aggregation proteolytic processing protein to occur length-dependent manner. In addition, we aberrant metabolism expanded be coupled cellular toxicity, indicating likely molecular basis for toxic gain function that produces neuronal degeneration SBMA.

The nucleus is the primary site of protein aggregation in many polyglutamine diseases, suggesting a central role pathogenesis. In SBMA, further implicated by critical for disease androgens, which promote nuclear translocation mutant androgen receptor (AR). To clarify importance we genetically manipulated localization signal polyglutamine-expanded AR. Transgenic mice expressing this AR displayed inefficient and substantially improved motor function compared with SBMA mice. While found that...

Spinal and bulbar muscular atrophy (SBMA) is a heritable neurodegenerative disease caused by the expansion of polyglutamine [poly(Q)] repeat within androgen receptor (AR) protein. We studied SBMA in Drosophila using an N-terminal fragment human AR Expression pathogenic protein with expanded poly(Q) results nuclear cytoplasmic inclusion formation, cellular degeneration, preferentially neuronal tissues. have influence ubiquitin-dependent modification proteasome pathway on neural degeneration...

Spinocerebellar ataxia type1 (SCA1) is one of several neurodegenerative disorders caused by expansions translated CAG trinucleotide repeats which code for polyglutamine in the respective proteins. Most hypotheses about molecular defect these suggest a gain function, may involve interactions with other proteins via expanded tract. In this study we used ataxin-1, SCA1 gene product, as bait yeast two-hybrid system and identified glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase an...

Spinobulbar muscular atrophy (SBMA) is an inherited neuromuscular disorder caused by the expansion of a CAG repeat encoding polyglutamine tract in exon 1 androgen receptor (AR) gene. SBMA demonstrates androgen-dependent toxicity due to unfolding and aggregation mutant protein. There are currently no disease-modifying therapies, but increasing interest for therapeutic targeting autophagy, highly conserved cellular process mediating protein quality control. We have previously shown that...

La Crosse virus causes a highly cytopathic infection in cultured cells and the murine central nervous system (CNS), with widespread neuronal destruction. In some viral infections of CNS, apoptosis, or programmed cell death, has been proposed as mechanism for cytopathology (Y. Shen T. E. Shenk, Curr. Opin. Genet. Dev. 5:105-111, 1995). To determine whether apoptosis plays role virus-induced we performed experiments newborn mice two neural tissue culture models. Newborn infected showed...

In polyglutamine diseases such as X-linked spinobulbar muscular atrophy (SBMA), it is unknown whether the toxic form of protein an insoluble or soluble aggregate a monomer. We have addressed this question by studying full-length androgen receptor (AR) mouse model SBMA. used biochemistry and atomic force microscopy to immunopurify oligomers after ultracentrifugation that are comprised single approximately 50-kDa N-terminal polyglutamine-containing AR fragment. appeared several weeks prior...

Aging is a risk factor for the development of adult-onset neurodegenerative diseases. Although some molecular pathways regulating longevity and stress resistance in lower organisms are defined (i.e., those activating transcriptional regulators DAF-16 HSF-1 <i>Caenorhabditis elegans</i>), their relevance to mammals disease susceptibility unknown. We studied signaling controlled by mammalian homolog DAF-16, FOXO3a, model systems motor neuron disease. Neuron death elicited <i>in vitro</i>...

Posttranslational protein modifications can play a major role in disease pathogenesis; phosphorylation, sumoylation, and acetylation modulate the toxicity of variety proteotoxic proteins. The androgen receptor (AR) is substantially modified, response to hormone binding, by acetylation; these might thus contribute DHT-dependent polyglutamine (polyQ)-expanded AR proteotoxicity spinal bulbar muscular atrophy (SBMA). SIRT1, nuclear deacetylase AR, neuroprotective many neurodegenerative models....

Expansion of the polyglutamine (polyQ) tract within androgen receptor (AR) causes neuromuscular degeneration in individuals with spinobulbar muscular atrophy (SBMA). PolyQ AR has diminished transcriptional function and exhibits ligand-dependent proteotoxicity, features that have both been implicated SBMA; however, extent to which altered contributes pathogenesis remains controversial. Here, we sought dissociate effects from polyQ-mediated proteotoxicity by enhancing activity polyQ AR. To...

Spinal and bulbar muscular atrophy (SBMA, Kennedy's disease) is one of a group progressive neurodegenerative diseases resulting from polyglutamine repeat expansion. In SBMA the polymorphic trinucleotide CAG in exon 1 androgen receptor (<i>AR</i>) gene increased, expansion tract. Patient autopsy material reveals neuronal intranuclear inclusions (NII) affected regions that contain only amino-terminal epitopes AR. Cell models have previously been unable to produce containing portion We report...

Abstract: Androgens are known to alter the morphology, survival, and axonal regeneration of lower motor neurons in vivo. To understand better molecular mechanisms androgen action neurons, we created a model system by stably expressing human receptor (AR) neuron hybrid cells. Motor cells express markers consistent with anterior horn can be differentiated into neuronal phenotype. When presence androgen, AR‐expressing cells, but not control exhibit dose‐dependent change morphology:...

Spinal and bulbar muscular atrophy (SBMA) is an inherited form of lower motor neuron degeneration caused by expansion a CAG repeat in the androgen receptor (AR) gene. To study mechanism which this mutation causes neuronal pathology, we stably transfected hybrid cell line with human AR cDNAs containing either 24 or 65 repeats (AR24 AR65, respectively). Both forms were able to bind ligand activate transcription reporter construct equally well. Likewise, subcellular localizations AR24 AR65...