Polyglutamine tract expansion of the androgen receptor in a motoneuronal model of spinal and bulbar muscular atrophy.
Spinobulbar muscular atrophy (SBMA) is a late-onset disorder characterized by progressive muscle loss, degeneration of motoneurons in the spinal cord and brainstem, and partial androgen insensitivity. SBMA is directly correlated with the expansion of CAG repeats encoding a polyglutamine tract (polyQ) of extended length. The identification of polyQ expansion in SBMA led to the discovery of an entire class of neurodegenerative disorders. In fact, at least eight different diseases, including Huntington's disease, share a common molecular mechanism involving an expansion of a polyQ tract within different proteins. The elongated polyQ tract causes a toxic gain of function in the mutant protein and is associated with the formation of intracellular aggregates, whose pathogenetic role has not been fully established yet. Our observations in a motoneuron cell line (NSC34), indicate that the expression of the androgen receptor (AR) carrying the elongated polyQ tract (AR-Q48) has a toxic effect in aggregate-independent manner. In fact, in basal condition, AR-Q48 shows a cytoplasmic diffuse distribution, yet it reduces the viability of transfected NSC34. In contrast, testosterone treatment, while inducing aggregation of the mutant AR, also increases cell viability. Aggregates in NSC34 are localized mainly in the perinuclear region and occasionally in the neuropil, whereas no nuclear aggregate has ever been found. Further observations of the minor subset of cells showing neuropil aggregates, reveal an alteration of the neurite morphology, suggesting a different role of the two types of cytoplasmic aggregates.
Piccioni
F
F
Institute of Endocrinology and Centre of Eccellence for the Study and Treatment of Neurodegenerative Diseases, University of Milan, Milano, Italy.
Simeoni
S
S
Andriola
I
I
Armatura
E
E
Bassanini
S
S
Pozzi
P
P
Poletti
A
A
D006801:Humans; D009046:Motor Neurons / Q000502:physiology*; D009134:Muscular Atrophy, Spinal / Q000235:genetics*; D009410:Nerve Degeneration / Q000235:genetics; D010455:Peptides / Q000235:genetics*; D011944:Receptors, Androgen / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion
D010455:Peptides; D011944:Receptors, Androgen; C097188:polyglutamine