Student’s Biochemical Society summer placement in IIB

Student’s Biochemical Society summer placement in IIB

Ravina Mistry, summer student working with James Torpey, supervised by Jill Madine and funded by Biochemical Society

Investigating peptide inhibition of alpha-synuclein as a potential therapeutic option for Lewy Body diseases

The two most common forms of dementia after Alzheimer’s disease are Dementia with Lewy bodies (DLB) and Parkinson’s disease (PD). These diseases are associated with intracellular inclusions of misfolded protein aggregates called Lewy bodies (LBs). The major protein component of LBs is the misfolded protein α-synuclein (asyn). Asyn and its associated aggregation/misfolding pathway is therefore a therapeutic target for these diseases. Collaborators in Bristol have identified a ten residue peptide that can prevent asyn aggregation and in turn prevent its associated toxicity. James had carried out NMR experiments to investigate the interaction between peptide and asyn and gain insight into the mode of action of the peptide in preventing aggregation. This data suggested that over time the peptide undergoes a structural rearrangement that is only detectable by a highly sensitive technique such as NMR, and that this is required before the peptide and protein are able to interact. This has implications for understanding the role of asyn aggregation in disease-associated toxicity and how it can be targeted therapeutically.

In her project Ravina investigated whether the peptide can also interact with and prevent aggregation of the six known disease associated mutants of asyn. Furthermore, she also used modified versions of the peptide (using amino acid substitutions) to further probe the mode of action and enhance the future progress of this peptide into a viable therapeutic avenue. She gained experience in a range of techniques including protein expression and purification, NMR, isothermal titration calorimetry, electron microscopy and fluorescence assays.

 

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