Mammalian ribosomal and chaperone protein RPS3A counteracts alpha-synuclein aggregation and toxicity in a yeast model system

摘要

Accumulation of aggregated forms of alpha Syn (alpha-synuclein) into Lewy bodies is a known hallmark associated with neuronal cell death in Parkinson's disease. When expressed in the yeast Saccharomyces cerevisiae, alpha Syn interacts with the plasma membrane, forms inclusions and causes a concentration-dependent growth defect. We have used a yeast mutant, cog6 Delta, which is particularly sensitive to moderate alpha Syn expression, for screening a mouse brain-specific cDNA library in order to identify mammalian proteins that counteract aSyn toxicity. The mouse ribosomal and chaperone protein RPS3A was identified as a suppressor of alpha Syn [WT (wild-type) and A53T] toxicity in yeast. We demonstrated that the 50 N-terminal amino acids are essential for this function. The yeast homologues of RPS3A were not effective in suppressing the alpha Syn-induced growth defect, illustrating the potential of our screening system to identify modifiers that would be missed using yeast gene overexpression as the first screening step. Co-expression of mouse RPS3A delayed the formation of alpha Syn-GFP inclusions in the yeast cells. The results of the present study suggest that the recently identified extraribosomal chaperonin function of RPS3A also acts on the neurodegeneration-related protein alpha Syn and reveal a new avenue for identifying promising candidate mammalian proteins involved in alpha Syn functioning.