Membrane Interactions of Oligomeric Alpha-Synuclein: Potential Role in Parkinsons Disease

Abstract

alpha-Synuclein is a small neuronal protein that has been implicated to play an important role in Parkinson's disease. Genetic mutations and multiplications in the alpha-synuclein gene can cause familial forms of the disease. In aggregated fibrillar form, alpha-synuclein is the main component of Lewy bodies, the intraneuronal inclusion bodies characteristic of Parkinson's disease. The loss of functional dopaminergic neurons in Parkinson's disease may be caused by a gain in toxic function of the protein. Elucidating if this gain of toxic function is related to the aggregation of alpha-synuclein may be vital in understanding Parkinson's disease. Although there are many ideas on how alpha-synuclein could be involved in the disease, this review will focus on the amyloid pore hypothesis. This hypothesis assumes that aggregation intermediates or oligomers are more likely to be toxic than monomeric or fibrillar forms of the protein. Oligomeric species are thought to exercise their toxicity through permeabilization of cellular membranes. Membrane pore formation by an oligomeric intermediate might play a role in other neurodegenerative disorders in which protein aggregation and amyloid formation play a role, such as Alzheimer's disease. We will discuss the role of this hypothesis in Parkinson's disease.

Extracellular Alpha-Synuclein Oligomers Induce Parkin S-Nitrosylation: Relevance to Sporadic Parkinson’s Disease Etiopathology

“…Recently, it was demonstrated that the negative impact of aberrantly secreted ASN does not appear to involve internalization of this protein by the recipient neurons [40,41], but it depends on deregulation of various plasma membrane receptors most of which are Ca 2+ channels [28,42,43]. Alternatively, aberrant oligomeric structures of ASN were shown to evoke permeabilization of cellular membranes leading to uncontrolled Ca 2+ influx and synaptic vesicular depletion [27,[44][45][46][47]. In our studies, we generated an oligomeric species of ASN that are able to form annular pore-like structures and observed that treatment of PC12 cells with those oligomers leads to significant increase in cellular Ca 2+ concentration.…”

Effects of intravenous immunoglobulin on alpha synuclein aggregation and neurotoxicity

“…α-Synuclein's cytotoxicity is thought to involve permeabilization of cell membranes [53,54]. This may be preceded by its binding to integrins (cell-surface glycoproteins) because treatment with an anti-integrin antibody, anti-integrin α5β1, partially rescues neuroblastoma cells from cell death after incubation with nitrated α-synuclein [55].…”

Conformations and Assembly of Amyloid Oligomers by Electrospray Ionisation - Ion Mobility Spectrometry - Mass Spectrometry

“…-syn is slightly expanded, lacking a tightly packed secondary structure but more compact than a fully expanded random coil [61]. Amyloid formation of -syn proceeds by a nucleation-dependent mechanism, in which the formation of a partially folded intermediate plays a critical role followed by several morphologically different types of aggregates, oligomers, amorphous aggregates and amyloid like fibrils [58][59][60]62].…”