Biology subjects

Wyant, C. E.

Publications and source records attributed to Wyant, C. E..

2 recordsLinked to original sources

bioRxiv2021

αS oligomers generated from polyunsaturated fatty acid and dopamine metabolite differentially interact with Aβ to enhance neurotoxicity

It is increasingly becoming clear that neurodegenerative diseases are not as discrete as originally thought to be but rather display significant overlap in histopathological and clinical presentations. For example, nearly half of the patients with Alzheimer disease (AD) and synucleinopathies such as Parkinson disease (PD) show symptoms and pathological features of one another. Yet, the molecular events and features that underlie such comorbidities in neurodegenerative diseases remain poorly understood. Here, inspired to uncover the molecular underpinnings of the overlap between AD and PD, we investigated the interactions between amyloid-{beta} (A{beta}) and -synuclein (S), aggregates of which form the major components of amyloid plaques and Lewy bodies, respectively. Specifically, we focused on S oligomers generated from the dopamine metabolite called dihydroxyphenylacetaldehyde (DOPAL), and a polyunsaturated fatty acid docosahexaenoic acid (DHA). Both S oligomers showed structural and conformational differences confirmed by their disparity in size, secondary structure, susceptibility to proteinase K digestion and cytotoxicity. More importantly, the two oligomers differentially modulated A{beta} aggregation. While both oligomers inhibited A{beta} aggregation to varying extents, they induced structurally different A{beta} assemblies. Furthermore, A{beta} seeded with DHA-derived S oligomers showed greater toxicity than DOPAL-derived S oligomers in SH-SY5Y neuroblastoma cells. These results provide insights into the interactions between two amyloid proteins with empirically distinctive biophysical and cellular manifestations, enunciating a basis for potentially ubiquitous cross-amyloid interactions across many neurodegenerative diseases.

biophysics↗

bioRxiv2020

Prion-like C-terminal domain of TDP-43 and α-Synuclein interact synergistically to generate neurotoxic hybrid fibrils

Aberrant aggregation and amyloid formation of tar DNA binding protein (TDP-43) and -synuclein (S) underlie frontotemporal dementia (FTD) and Parkinsons disease (PD), respectively. Amyloid inclusions of TDP-43 and S are also commonly co-observed in amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies (DLB) and Alzheimer disease (AD). Emerging evidence from cellular and animal models show colocalization of the TDP-43 and S aggregates, raising the possibility of direct interactions and co-aggregation between the two proteins. In this report, we set out to answer this question by investigating the interactions between S and prion-like pathogenic C-terminal domain of TDP-43 (TDP-43 PrLD). PrLD is an aggregation-prone fragment generated both by alternative splicing as well as aberrant proteolytic cleavage of full length TDP-43. Our results indicate that two proteins interact in a synergistic manner to augment each others aggregation towards hybrid fibrils. While monomers, oligomers and sonicated fibrils of S seed TDP-43 PrLD monomer aggregation, TDP-43 PrLD fibrils failed to seed S monomers indicating selective interactions. Furthermore, S modulates liquid droplets formed by TDP-43 PrLD and RNA to promote insoluble amyloid aggregates. Importantly, the cross-seeded hybrid aggregates show greater cytotoxicity as compared to the individual homotypic aggregates suggesting that the interactions between the two proteins have a discernable impact on cellular functions. Together, these results bring forth insights into TDP-43 PrLD - S interactions that could help explain clinical and pathological presentations in patients with co-morbidities involving the two proteins.

biophysics↗