Elsevier

Neurobiology of Disease

Volume 176, January 2023, 105966
Neurobiology of Disease

Review
Monitoring α-synuclein aggregation

https://doi.org/10.1016/j.nbd.2022.105966Get rights and content
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Abstract

Synucleinopathies, including Parkinson's disease (PD), dementia with Lewy Bodies (DLB), and multiple system atrophy (MSA), are characterized by the misfolding and subsequent aggregation of alpha-synuclein (α-syn) that accumulates in cytoplasmic inclusions bodies in the cells of affected brain regions. Since the seminal report of likely-aggregated α-syn presence within the Lewy bodies by Spillantini et al. in 1997, the keyword “synuclein aggregation” has appeared in over 6000 papers (Source: PubMed October 2022). Studying, observing, describing, and quantifying α-syn aggregation is therefore of paramount importance, whether it happens in tubo, in vitro, in post-mortem samples, or in vivo. The past few years have witnessed tremendous progress in understanding aggregation mechanisms and identifying various polymorphs. In this context of growing complexity, it is of utmost importance to understand what tools we possess, what exact information they provide, and in what context they may be applied. Nonetheless, it is also crucial to rationalize the relevance of the information and the limitations of these methods for gauging the final result. In this review, we present the main techniques that have shaped the current views about α-syn structure and dynamics, with particular emphasis on the recent breakthroughs that may change our understanding of synucleinopathies.

Keywords

Synucleinopathy
Parkinson's disease
α-Synuclein
Oligomerization
Fibril
Amyloid
Fluorescence
Polymorphism
Structural techniques

Abbreviations

Ab
Antibody
AFM
Atomic Force Microscopy
α-syn
alpha-synuclein
AS-PLA
Alpha-synuclein Proximity Ligation Assay
BiFC
Bimolecular Fluorescence Complementation
CD
Circular Dichroism
CFP
Cyan Fluorescent Protein
CR
Congo Red
CSF
Cerebro-spinal fluid
cryo-EM
Cryogenic Electron Microscopy
Cys-Mal
cysteine residue labelled via fluorophore-attached maleimides
DLB
Dementia with Lewy Bodies
ED
Electron diffraction
ELISA
Enzyme-Linked Immunosorbent Assay
EM
Electron Microscopy
ESIPT
Excited-State Intramolecular Proton-Transfer
FlAsH
Fluorescein Arsenical Hairpin
FRET
Förster Resonance Energy Transfer
FTIR
Fourier-Transformed Infra-Red
GCI
Glial Cytoplasmic Inclusions
GFP
Green Fluorescent Protein
LB
Lewy body
LCPs
Luminescent Conjugated Polymers
LRP
Lewy-related pathology
MicroED
Microcrystal Electron Diffraction
mAb
Monoclonal Antibody
MSA
Multiple System Atrophy
NDGA
nordihydroguaiaretic acid
NMR
Nuclear Magnetic Resonance
PCA
Protein Complementation Assay
PD
Parkinson's Disease
PMCA
protein misfolding cyclic amplification
PFF
Pre-Formed Fibril
PK
Proteinase K
ReAsH
Red Arsenical Hairpin
RT-QuIC
real-time quaking-induced conversion
smFRET
single-molecule Förster Resonance Energy Transfer
ssNMR
Solid-State Nuclear Magnetic Resonance
ThS
Thioflavine S
ThT
Thioflavine T
UAA
Unnatural Amino Acid
VCD
Vibrational Circular Dichroism

Data availability

No data was used for the research described in the article.

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