α‐synuclein oligomers and fibrils: a spectrum of species, a spectrum of toxicities
2019/06/29 by Parvez Alam, Luc Bousset, Ronald Melki +1 · 30 citations
Medicine · #Parkinson's Disease Mechanisms and Treatments #Neurological disorders and treatments #Botulinum Toxin and Related Neurological Disorders
paper · pdf · doi:10.1111/jnc.14808
Abstract
This review article provides an overview of the different species that α-synuclein aggregates can populate. It also attempts to reconcile conflicting views regarding the cytotoxic roles of oligomers versus fibrils. α-synuclein, while highly dynamic in the monomeric state, can access a large number of different assembly states. Depending on assembly conditions, these states can interconvert over different timescales. The fibrillar state is the most thermodynamically favored due to the many stabilizing interactions formed between each monomeric unit, but different fibrillar types form at different rates. The end distribution is likely to reflect kinetic partitioning as much as thermodynamic equilibra. In addition, metastable oligomeric species, some of which are on-pathway and others off-pathway, can be populated for remarkably long periods of time. Chemical modifications (phosphorylation, oxidation, covalent links to ligands, etc.) perturb these physical interconversions and invariably destabilize the fibrillar state, leading to small prefibrillar assemblies which can coalesce into amorphous states. Both oligomeric and fibrillar species have been shown to be cytotoxic although firm conclusions require very careful evaluation of particle concentrations and is complicated by the great variety and heterogeneity of different experimentally observed states. The mechanistic relationship between oligomers and fibrils remains to be clarified, both in terms of assembly of oligomers into fibrils and potential dissolution of fibrils into oligomers. While oligomers are possibly implicated in the collapse of neuronal homeostasis, the fibrillar state(s) appears to be the most efficient at propagating itself both in vitro and in vivo, pointing to critical roles for multiple different aggregate species in the progression of Parkinson's disease (https://onlinelibrary.wiley.com/page/journal/14714159/homepage/virtualissues.htm). This article is part of the Special Issue "Synuclein".
Cited by
- Distinct alpha‐Synuclein species induced by seeding are selectively cleared by the Lysosome or the Proteasome in neuronally differentiated SH‐SY5Y cells
- Randomized Phase I Trial of the α‐Synuclein Antibody Lu AF82422
- The Importance of Being Imperfect: Structure and Function of Bacterial Amyloid
- Natural Design of a Stabilized Cross‐β Fold: Structure of the FuA FapC from Pseudomonas Sp. UK4 Reveals a Critical Role for Stacking of Imperfect Repeats
- α-Synuclein induces Th17 differentiation and impairs the function and stability of Tregs by promoting RORC transcription in Parkinson's disease
- The Overcrowded Crossroads: Mitochondria, Alpha-Synuclein, and the Endo-Lysosomal System Interaction in Parkinson's Disease. [europepmc]
- A simple, versatile and robust centrifugation-based filtration protocol for the isolation and quantification of α-synuclein monomers, oligomers and fibrils: Towards improving experimental reproducibility in α-synuclein research. [europepmc]
- Alpha-Synuclein Physiology and Pathology: A Perspective on Cellular Structures and Organelles. [europepmc]
- Modeling Parkinson's Disease With the Alpha-Synuclein Protein. [europepmc]
- Soluble endogenous oligomeric α-synuclein species in neurodegenerative diseases: Expression, spreading, and cross-talk. [europepmc]
- Computational prediction of protein aggregation: Advances in proteomics, conformation-specific algorithms and biotechnological applications. [europepmc]
- The Role of Lipids in the Initiation of α-Synuclein Misfolding. [europepmc]
- The Endoplasmic Reticulum Stress/Unfolded Protein Response and Their Contributions to Parkinson's Disease Physiopathology. [europepmc]
- Glycogen Synthase Kinase 3β: A New Gold Rush in Anti-Alzheimer's Disease Multitarget Drug Discovery? [europepmc]
- NMR unveils an N-terminal interaction interface on acetylated-α-synuclein monomers for recruitment to fibrils. [europepmc]
- The structural heterogeneity of α-synuclein is governed by several distinct subpopulations with interconversion times slower than milliseconds. [europepmc]
- Safety and Tolerability of Active Immunotherapy Targeting α-Synuclein with PD03A in Patients with Early Parkinson's Disease: A Randomized, Placebo-Controlled, Phase 1 Study. [europepmc]
- Phenotypic manifestation of α-synuclein strains derived from Parkinson's disease and multiple system atrophy in human dopaminergic neurons. [europepmc]
- The Prion-Like Spreading of Alpha-Synuclein in Parkinson's Disease: Update on Models and Hypotheses. [europepmc]
- Alpha-Synuclein defects autophagy by impairing SNAP29-mediated autophagosome-lysosome fusion. [europepmc]
- Alpha-Synuclein PET Tracer Development-An Overview about Current Efforts. [europepmc]
- Midbrain organoids with an SNCA gene triplication model key features of synucleinopathy. [europepmc]
- Microglia-specific overexpression of α-synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity. [europepmc]
- Effects of oligomer toxicity, fibril toxicity and fibril spreading in synucleinopathies. [europepmc]
- Initiation and progression of α-synuclein pathology in Parkinson's disease. [europepmc]
- GBA Variants and Parkinson Disease: Mechanisms and Treatments. [europepmc]
- Mechanisms of enhanced aggregation and fibril formation of Parkinson's disease-related variants of α-synuclein. [europepmc]
- Alpha-Synuclein Aggregation Pathway in Parkinson's Disease: Current Status and Novel Therapeutic Approaches. [europepmc]
- Iron Brain Menace: The Involvement of Ferroptosis in Parkinson Disease. [europepmc]
- Alpha Synuclein: Neurodegeneration and Inflammation. [europepmc]
Related