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|Title: ||Motorneuron degeneration in Spinal and Bulbar Muscular Atrophy: from the molecular mechanisms to the potential therapeutical approaches|
|Authors: ||RUSMINI, PAOLA|
|Presentation date: ||Mar-2011|
|Abstract: ||Spinobulbar muscular atrophy (SBMA) is an X-linked motorneuronal disease, caused by a polyglutamine (polyQ) elongation in the androgen receptor (AR) protein, which induces motor neuron loss in the spinal cord and in the bulbar region. In SBMA, the mutant ARpolyQ become neurotoxic after its interaction with the physiological ligand testosterone (T). The binding with T, is known to induce AR activation, dimerization and translocation into the nucleus. In the ARpolyQ, this mechanism is possibly associated with the acquisition of aberrant conformations (misfolding) and T induces ARpolyQ aggregation. The aggregates contain components of the ubiquitin/proteasome pathway (UPS) and Heat shock proteins (Hsps), suggesting a possibile involvement of UPS in SBMA.
Using SBMA motor neuronal cell models (NSC34) expressing wt and mutant AR, we found that the non-activated and soluble ARpolyQ impaired UPS activity. T-activated ARpolyQ aggregated resulting in an improvement of UPS activity. Thus ARpolyQ aggregates might serve to segregate misfolded species into physically defined intracellular compartments (the aggregates) waiting for an alternative degradative pathway, such as autophagy. This was confirmed by analysing the intracellular distribution of the autophagic marker LC3. In fact, in presence of the T-activated mutant ARpolyQ, LC3 showed an intense punctate staining, suggesting that autophagy is involved in the clearance of this mutant protein.
We then used two different approaches to counteract ARpolyQ toxicity by increasing its clearance via the two intracellular proteolytic systems.
In the first approach, we overexpressed the small HspB8, and found that this chaperone decreased the intracellular levels of the mutant ARpolyQ and completely counteracted ARpolyQ aggregation. We demonstrated that HspB8 acts without affecting the UPP, but facilitates the ARpolyQ clearance via the autophagic pathway. In fact, HspB8 stimulated the LC3-II formation, and increased the number of autophagosomes. LC3 silencing correlated with the loss of HspB8 prodegradative effects on ARpolyQ. HspB8 action appeared to be mediated by a heterocomplex with other chaperones, as Bag3, Hsc70 and CHIP.
In the scond approach, we analysed the effects of the Hsp90 inhibitor 17-Allylamino-17-demethoxygeldanamycin (17-AAG) on ARpolyQ degradation. 17-AAG has already been found capable to reduce ARpolyQ toxicity in SBMA transgenic mice. In our SBMA model, 17-AAG reduced ARpolyQ aggregation by stimulation ARpolyQ clearance without altering the UPS activity. 17-AAG induced LC3 expression, increased LC3 turnover and LC3 punctate distribution both in absence and in presence of T. Moreover, 17-AAG action is blocked both by pharmacological autophagic inhibition (3-MA) and by LC3-silencing, suggesting a relevant role for 17-AAG in the induction of autophagy.
Together these data suggest that compounds capable to potentiate ARpolyQ clearance via autophagy may have useful application in SBMA.|
|MIUR subjects: ||BIO/13 - Biologia Applicata|
|Citation: ||Motorneuron degeneration in Spinal and Bulbar Muscular Atrophy: from the molecular mechanisms to the potential therapeutical approaches / P. Rusmini, V. Crippa, D. Sau, S. Guareschi, A. Poletti. ((Intervento presentato al 16. convegno Telethon Convention tenutosi a RIVA DEL GARDA nel 2011.|
|Type: ||Conference Object|
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