α-Synuclein oligomers and fibrils: partners in crime in synucleinopathies

Abstract

The misfolding and aggregation of α-synuclein is the general hallmark of a group of devastating neurodegenerative pathologies referred to as synucleinopathies, such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. In such conditions, a range of different misfolded aggregates, including oligomers, protofibrils, and fibrils, are present both in neurons and glial cells. Growing experimental evidence supports the proposition that soluble oligomeric assemblies, formed during the early phases of the aggregation process, are the major culprits of neuronal toxicity; at the same time, fibrillar conformers appear to be the most efficient at propagating among interconnected neurons, thus contributing to the spreading of α-synuclein pathology. Moreover, α-synuclein fibrils have been recently reported to release soluble and highly toxic oligomeric species, responsible for an immediate dysfunction in the recipient neurons. In this review, we discuss the current knowledge about the plethora of mechanisms of cellular dysfunction caused by α-synuclein oligomers and fibrils, both contributing to neurodegeneration in synucleinopathies.

Linking acetylated α-Tubulin redistribution to α-Synuclein pathology in brain of Parkinson’s disease patients

“…The presence of neurons displaying the enrichment of acetylated α-Tubulin in cell bodies and lacking mature LBs inside them, let us to hypothesize that the observed change in acetylated α-Tubulin could be involved in the initial step of α-Synuclein aggregation. We therefore focused on α-Synuclein oligomers 66 , the earliest α-Synuclein aggregated species 36 , 67 , 68 . Using super-resolution microscopy, we found a staging-like distribution between α-Synuclein and acetylated α-Tubulin.…”

Targets to Search for New Pharmacological Treatment in Idiopathic Parkinson’s Disease According to the Single-Neuron Degeneration Model

“…Alpha-synuclein oligomers induce synaptic impairment, endoplasmic reticulum stress, mitochondrial dysfunction, loss of regulation of proteostasis, neuroinflammation, cell apoptosis, lysosomal dysfunction, oxidative stress, and autophagy impairment [ 27 , 44 , 45 , 46 , 47 , 48 ]. However, the propagative nature of alpha-synuclein [ 49 ] will imply rapid neurodegeneration of the nigrostriatal system when neurotoxic oligomers are formed, which is the opposite of what occurs in the disease. Mutations in the alpha-synuclein gene induce the formation of neurotoxic alpha-synuclein oligomers in familial Parkinson’s disease that are transmitted to neighboring neurons through exosomes [ 49 , 50 , 51 , 52 ].…”

“…However, the propagative nature of alpha-synuclein [ 49 ] will imply rapid neurodegeneration of the nigrostriatal system when neurotoxic oligomers are formed, which is the opposite of what occurs in the disease. Mutations in the alpha-synuclein gene induce the formation of neurotoxic alpha-synuclein oligomers in familial Parkinson’s disease that are transmitted to neighboring neurons through exosomes [ 49 , 50 , 51 , 52 ]. Alpha-synuclein alone does not aggregate into neurotoxic oligomers and the question is what induces the aggregation of alpha-synuclein to neurotoxic oligomers in neuromelanin-containing dopaminergic neurons in the nigrostriatal system in idiopathic Parkinson’s disease.…”

The Toxicity of Protein Aggregates: New Insights into the Mechanisms

“…They emphasized the proposition that oligomeric species have more inherent abilities to promptly induce cellular dysfunction and neurotoxicity, while fibrillar conformers are more effective in spreading from neuron to neuron, thus propagating neurodegeneration, as depicted in Figure 1, "cellular mechanisms of neurotoxicity". These conclusions arise from experimental evidences by several researchers, including ourselves, on the prominent neurotoxic potential of oligomeric species, which are not only formed during αS aggregation, but are also released by mature fibrils upon their interaction with the neuronal membrane [4][5][6][7]. The review by Gracia et al presents the state-of-the-art knowledge on αS aggregation and toxicity, which is extremely useful for hypothesizing therapeutic drugs and diagnostic tools for accurate diagnoses.…”