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 correla ted 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, a t least eight different diseases, including Huntington's disease, share a c ommon molecular mechanism involving an expansion of a polyQ tract within di fferent proteins. The elongated polyQ tract causes a toxic gain of function in the mutant protein and is associated with the formation of intracellula r aggregates, whose pathogenetic role has not been fully established yet. O ur observations in a motoneuron cell line (NSC34), indicate that the expres sion of the androgen receptor (AR) carrying the elongated polyQ tract (AR-Q 48) has a toxic effect in aggregate-independent manner. In fact, in basal c ondition, AR-Q48 shows a cytoplasmic diffuse distribution, yet it reduces t he viability of transfected NSC34. In contrast, testosterone treatment, whi le inducing aggregation of the mutant AR, also increases cell viability. Ag gregates in NSC34 are localized mainly in the perinuclear region and occasi onally in the neuropil, whereas no nuclear aggregate has ever been found. F urther observations of the minor subset of cells showing neuropil aggregate s, reveal an alteration of the neurite morphology, suggesting a different r ole of the two types of cytoplasmic aggregates. (C) 2001 Elsevier Science I nc.