Cross-interactions of DOPAL derived ɑ-synuclein oligomers with amyloid-β: Implications for comorbidities in neurodegenerative diseases

Protein misfolding and amyloid aggregation are key features of neurodegenerative diseases such as Alzheimer disease (AD), Parkinson’s disease (PD). Amyloid aggregates in form of the extracellular plaques formed by the protein amyloid-b (Ab), and intracellular neurofibrillary tangles by tau are hallmarks of AD pathology, while cytoplasmic inclusions containing a-Synuclein (aS) aggregates called Lewy bodies are present in PD. The aggregation of amyloidogenic proteins involve formation of oligomers and fibrillar aggregates, responsible for neuronal death. In the last decades, it has come to light that AD and PD patients show comorbidities and that amyloid inclusions containing of both Ab and aS are present in the patient brains. We hypothesized that there is an interplay between these two proteins at the molecular level. In this study, we investigated the interaction between oligomers of aS with Ab. Specifically, recombinant purification of monomeric ɑ-synuclein was done using Ni-NTA affinity chromatography followed by size-exclusion chromatography (SEC), the generation of aS oligomers induced by dihydroxyphenyl acetaldehyde (DOPAL), an important metabolite was conducted followed by monioting its interaction with Ab monomers by biophysical methods. The results indicate that aS oligomers delay the aggregation Ab monomers and potentially generating toxic intermediates. This study showcases the potential crosstalks between amyloidogenic proteins which are increasingly observed in neurodegenerative diseases.