Cyclodextrins enhance the solubility and the turnover of aggregation prone proteins

Cyclodextrins (Cdx) are cyclic oligosaccharides validated as artificial chaperones for the proper protein refolding. Natural chaperones like the Heat Shock Proteins (Hsp) are involved in the quality control of the proteins, preventing misfolding, assisting the refolding or addressing to the degradation systems. It was demonstrated that the Hsps overexpression, also prevented aggregation of aberrant proteins, maintaining them in a soluble state, competent for a rapid degradation. Protein aggregation in insoluble inclusions is the hallmark of many degenerative diseases. We focused our attention on two diseases characterized by motoneuron death, Amyotrophic Lateral Sclerosis (ALS) and Spinobulbar Muscular Atrophy (SBMA). In our model of ALS we transiently expressed mutant SOD1 (SODG93A), an enzyme found mutated in 10% familial ALS cases (fALS), in immortalized motoneurons (NSC34). Our models of SBMA are based on the expression of the androgen receptor with an abnormal expansion of the polyglutamine tract (ARPolyQ) which characterize all cases of SBMA. ARPolyQ was, therefore, transiently transfected in NSC34 or stably expressed in PC12 cells, in response to doxycycline. The protein quality control system in our models was found impaired, causing proteasome saturation and ineffective clearance that possibly led to protein aggregation. We, therefore, tested the effect of Cdx on SODG93A and ARPolyQ. We investigated their role in decreasing the aggregation and the proteasome impairment using a YFPu reporter system. We found evidence that Cdx were effective in decreasing the mutant proteins inclusions keeping them soluble. Moreover, this compound enhanced the turnover of both SODG93A and ARPolyQ, increasing the protein degradation and desaturating the proteasome, even in presence of the inhibitor MG132. Cdx may, therefore, enhance alternative degradation pathways, such as autophagy and may be an interesting candidate to counteract the toxicity mediated by misfolded proteins.