Role of Sporadic Parkinson Disease Associated Mutations A18T and A29S in Enhanced α-Synuclein Fibrillation and Cytotoxicity

Deposition of pre-synaptic protein α-synuclein in Lewy bodies and Lewy neurites in the substantia nigra region of brain has been linked with the clinical symptoms of the Parkinson’s disease (PD). Proteotoxic stress conditions and mutations that cause abnormal aggregation of α-synuclein have close association with onset of PD and its progression. Therefore, studies pertaining to α-synuclein mutations play important roles in mechanistic understanding of aggregation behaviour of the protein and subsequent pathology. Herein, guided by this fact, we have studied the aggregation kinetics, morphology and neurotoxic effects of the two newly discovered sporadic PD associated mutants A18T and A29S of α- synuclein. Our studies demonstrate that both of the mutants are aggregation prone and undergo rapid aggregation compared to wild type α-synuclein. Further, it was found that A18T mutant follow faster aggregation kinetics compared to A29S substitution. Additionally, we have designed three point mutations of α-synuclein for better understanding of the effects of substitutions on protein aggregation and demonstrate that substitution of alanine at 18 th position is highly sensitive compared to adjacent positions. Our results provide better understanding on the effects of α-synuclein mutations on its aggregation behaviour that may be important in development of PD pathology.

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