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  • 1
    Electronic Resource
    Electronic Resource
    Kennedy's Disease (1999)
    Oxford UK : Blackwell Science Ltd.
    Journal of neurochemistry 72 (1999), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract : X-linked spinal and bulbar muscular atrophy (SBMA),Kennedy's disease, is a degenerative disease of the motor neurons that isassociated with an increase in the number of CAG repeats encoding apolyglutamine stretch within the androgen receptor (AR). Recent work hasdemonstrated that the gene products associated with open reading frame tripletrepeat expansions may be substrates for the cysteine protease cell deathexecutioners, the caspases. However, the role that caspase cleavage plays inthe cytotoxicity associated with expression of the disease-associated allelesis unknown. Here, we report the first conclusive evidence that caspasecleavage is a critical step in cytotoxicity ; the expression of the AR with anexpanded polyglutamine stretch enhances its ability to induce apoptosis whencompared with the normal AR. The AR is cleaved by a caspase-3 subfamilyprotease at Asp146, and this cleavage is increased duringapoptosis. Cleavage of the AR at Asp146 is critical for theinduction of apoptosis by AR, as mutation of the cleavage site blocks theability of the AR to induce cell death. Further, mutation of the caspasecleavage site at Asp146 blocks the ability of the SBMA AR to form perinuclear aggregates. These studies define a fundamental role for caspase cleavage in the induction of neural cell death by proteins displaying expanded polyglutamine tracts, and therefore suggest a strategy that may be useful to treat neurodegenrative diseases associated with polyglutamine repeat expansions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1999.0720185.x
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  • 2
    Electronic Resource
    Electronic Resource
    Reduced transcriptional regulatory competence of the androgen receptor in X–linked spinal and bulbar muscular atrophy (1993)
    [s.l.] : Nature Publishing Group
    Nature genetics 5 (1993), S. 184-188 
    Details
    ISSN: 1546-1718
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Medicine
    Notes: [Auszug] Expansion of the long (CAG; glutamine)n repeat in the first exon of the X–linked human androgen receptor gene (hAR) causes spinal and bulbar muscular atrophy, frequently in association with mild androgen insensitivity. The relevant normal motor neurons are preferentially stimulated by ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/ng1093-184
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  • 3
    Electronic Resource
    Electronic Resource
    Codon-usage variants in the polymorphic (GGN) n trinucleotide repeat of the human androgen receptor gene (1997)
    Springer
    Human genetics 〈Berlin〉 101 (1997), S. 43-46 
    Details
    ISSN: 1432-1203
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The human androgen receptor gene (hAR) has a long, polymorphic trinucleotide (GGN; glycine) n repeat in the 3′ portion of its first exon, with n = 10–31. Owing to technical difficulties that have precluded routine sequencing of this region, it is widely unknown that N represents T, G or C, and that the usual sense codon sequence of the GGN tract is (GGT)3GGG(GGT)2(GGC)4–25. Furthermore, on 4 of 61 X chromosomes, we observed that the internal GGT sequence was present three or four times instead of twice. Strikingly, each of the three alleles with an internal (GGT)3, and only these three, also had a (GGC)20 repeat. The size or composition of a (GGN) n repeat was not correlated with the length of the accompanying (CAG) n CAA repeat in the 5′ portion of exon one. Hence, codon-usage variants of the GGN tract may be used to seek associations with particular diseases, as diagnostic aids in families with androgen insensitivity whose AR mutations have not yet been identified, or as internal controls for observations on intergenerational contractions or expansions of the (CAG) n CAA tract in a given hAR allele.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004390050583
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  • 4
    Electronic Resource
    Electronic Resource
    Increased T-type Ca2+ channel activity as a determinant of cellular toxicity in neuronal cell lines expressing polyglutamine-expanded human androgen receptors (2000)
    Springer
    Molecular and cellular biochemistry 203 (2000), S. 23-31 
    Details
    ISSN: 1573-4919
    Keywords: T-type Ca2+ channel ; polyglutamine-expanded androgen receptor ; CAG trinucleotide repeats ; spinobulbar muscular atrophy ; apoptosis ; motorneuron ; cell lines ; neuroblastoma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract We have analyzed Ca2+ currents in two neuroblastoma-motor neuron hybrid cell lines that expressed normal or glutamine-expanded human androgen receptors (polyGln-expanded AR) either transiently or stably. The cell lines express a unique, low-threshold, transient type of Ca2+ current that is not affected by L-type Ca2+ channel blocker (PN 200-110), N-type Ca2+ channel blocker (ω-conotoxin GVIA) or P-type Ca2+ channel blocker (Agatoxin IVA) but is blocked by either Cd2+ or Ni2+. This pharmacological profile most closely resembles that of T-type Ca2+ channels [1-3]. Exposure to androgen had no effect on control cell lines or cells transfected with normal AR but significantly changed the steady-state activation in cells transfected with expanded AR. The observed negative shift in steady-state activation results in a large increase in the T-type Ca2+ channel window current. We suggest that Ca2+ overload due to abnormal voltage-dependence of transient Ca2+ channel activation may contribute to motor neuron toxicity in spinobulbar muscular atrophy (SBMA). This hypothesis is supported by the additional finding that, at concentrations that selectively block T-type Ca2+ channel currents, Ni2+ significantly reduced cell death in cell lines transfected with polyGln-expanded AR.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007010020228
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