Motoneuronal cell death is not correlated with aggregate formation of androgen receptors containing an elongated polyglutamine tract.
Spinal and bulbar muscular atrophy (SBMA) is associated with an abnormal expansion of the (CAG)(n)repeat in the androgen receptor (AR) gene. Similar mutations have been reported in other proteins that cause neurodegenerative disorders. The CAG-coded elongated polyglutamine (polyGln) tracts induce the formation of neuronal intracellular aggregates. We have produced a model to study the effects of potentially 'neurotoxic' aggregates in SBMA using immortalized motoneuronal cells (NSC34) transfected with AR containing polyGln repeats of different sizes [(AR.Q(n = 0, 23 or 46)]. Using chimeras of AR.Q(n) and the green fluorescent protein (GFP), we have shown that aggregate formation occurs when the polyGln tract is elongated and AR is activated by androgens. In NSC34 cells co-expressing the AR with the polyGln of pathological length (AR.Q46) and the GFP we have noted the presence of several dystrophic neurites. Cell viability analyses have shown a reduced growth/survival rate in NSC34 expressing the AR.Q46, whereas testosterone treatment partially counteracted both cell death and the formation of dystrophic neurites. These observations indicate the lack of correlation between aggregate formation and cell survival, and suggest that neuronal degeneration in SBMA might be secondary to axonal/dendritic insults.
Simeoni
S
S
Istituto di Endocrinologia, Università di Milano, via Balzaretti 9, 20133 Milano, Italy.
Mancini
M A
MA
Stenoien
D L
DL
Marcelli
M
M
Weigel
N L
NL
Zanisi
M
M
Martini
L
L
Poletti
A
A
D000818:Animals; D001483:Base Sequence; D016923:Cell Death / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D049452:Green Fluorescent Proteins; D006822:Hybrid Cells; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000166:cytology / Q000473:pathology*; D009133:Muscular Atrophy / Q000235:genetics / Q000473:pathology; D009410:Nerve Degeneration / Q000235:genetics; D009447:Neuroblastoma / Q000196:embryology / Q000473:pathology; D010455:Peptides / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology / Q000196:embryology
D008164:Luminescent Proteins; D010455:Peptides; D011944:Receptors, Androgen; D011994:Recombinant Proteins; D049452:Green Fluorescent Proteins; C097188:polyglutamine