title: Dopamine-induced α-synuclein oligomers show self- and cross-propagation properties.
abstract: Amyloid aggregates of α-synuclein (αS) protein are the predominant species present within the intracellular inclusions called Lewy bodies in Parkinson's disease (PD) patients. Among various aggregates, the low-molecular weight ones broadly ranging between 2 and 30 mers are known to be the primary neurotoxic agents responsible for the impairment of neuronal function. Recent research has indicated that the neurotransmitter dopamine (DA) is one of the key physiological agents promoting and augmenting αS aggregation, which is thought to be a significant event in PD pathologenesis. Specifically, DA is known to induce the formation of soluble oligomers of αS, which in turn are responsible for inducing several important cellular changes leading to cellular toxicity. In this report, we present the generation, isolation, and biophysical characterization of five different dopamine-derived αS oligomers (DSOs) ranging between 3 and 15 mers, corroborating previously published reports. More importantly, we establish that these DSOs are also capable of replication by self-propagation, which leads to the replication of DSOs upon interaction with αS monomers, a process similar to that observed in mammilian prions. In addition, DSOs are also able to cross-propagate amyloid-β (Aβ) aggregates involved in Alzheimer's disease (AD). Interestingly, while self-propagation of DSOs occur with no net gain in protein structure, cross-propagation proceeds with an overall gain in β-sheet conformation. These results implicate the involvement of DSOs in the progression of PD, and, in part, provide a molecular basis for the observed co-existence of AD-like pathology among PD patients.
authors.affiliation: Department of Chemistry and Biochemistry, University of Southern Mississippi, Hattiesburg, Mississippi, 39406.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Planchard
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Exley
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Morgan
authors.forename: Vijayaraghavan
authors.initials: V
authors.lastname: Rangachari
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D002942:Circular Dichroism; D004298:Dopamine / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D011328:Prions / Q000737:chemistry* / Q000378:metabolism; D017433:Protein Structure, Secondary; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D011328:Prions; D051844:alpha-Synuclein; D004298:Dopamine
keywords: Parkinson's; amyloid; oligomers; prion; propagation; α-synuclein