The chaperonin CCT inhibits assembly of α-synuclein amyloid fibrils by a specific, conformation-dependent interaction

The eukaryotic chaperonin CCT (chaperonin containing TCP-1) uses cavities built into its double-ring structure to encapsulate and to assist folding of a large subset of proteins. CCT can inhibit amyloid fibre assembly and toxicity of the polyQ extended mutant of huntingtin, the protein responsible for Huntington's disease. This raises the possibility that CCT modulates other amyloidopathies, a stillun-addressed question. We show here that CCT inhibits amyloid fibre assembly of alpha-synuclein A53T, one of the mutants responsible for Parkinson's disease. We evaluated fibrillation blockade in alpha-synuclein A53T deletion mutants and CCT interactions of full-length A53T in distinct oligomeric states to define an inhibition mechanism specific for alpha-synuclein. CCT interferes with fibre assembly by interaction of its CCT. and CCT. subunits with the A53T central hydrophobic region (NAC). This interaction is specific to NAC conformation, as it is produced once soluble alpha-synuclein A53T oligomers form and blocks the reaction before fibres begin to grow. Finally, we show that this association inhibits alpha-synuclein A53T oligomer toxicity in neuroblastoma cells. In summary, our results and those for huntingtin suggest that CCT is a general modulator of amyloidogenesis via a specific mechanism.