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An Update on the Critical Role of α-Synuclein in Parkinson’s Disease and Other Synucleinopathies: from Tissue to Cellular and Molecular Levels

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Abstract

The aggregation of alpha-synuclein (α-Syn) plays a critical role in the development of Parkinson’s disease (PD) and other synucleinopathies. α-Syn, which is encoded by the SNCA gene, is a lysine-rich soluble amphipathic protein normally expressed in neurons. Located in the cytosolic domain, this protein has the ability to remodel itself in plasma membranes, where it assumes an alpha-helix conformation. However, the protein can also adopt another conformation rich in cross-beta sheets, undergoing mutations and post-translational modifications, then leading the protein to an unusual aggregation in the form of Lewy bodies (LB), which are cytoplasmic inclusions constituted predominantly by α-Syn. Pathogenic mechanisms affecting the structural and functional stability of α-Syn — such as endoplasmic reticulum stress, Golgi complex fragmentation, disfunctional protein degradation systems, aberrant interactions with mitochondrial membranes and nuclear DNA, altered cytoskeleton dynamics, disrupted neuronal plasmatic membrane, dysfunctional vesicular transport, and formation of extracellular toxic aggregates — contribute all to the pathogenic progression of PD and synucleinopathies. In this review, we describe the collective knowledge on this topic and provide an update on the critical role of α-Syn aggregates, both at the cellular and molecular levels, in the deregulation of organelles affecting the cellular homeostasis and leading to neuronal cell death in PD and other synucleinopathies.

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Abbreviations

6-OHDA:

6-Hydroxydopamine

α-Syn:

Alpha-Synuclein

AGEs:

Advanced glycation end products

ATF:

Cyclic AMP-dependent transcription factor

AVV:

Adeno-associated virus

CMA:

Chaperone-mediated autophagy

CNS:

Central nervous system

CHMP2B:

Charged multivesicular body protein 2B

CHOP:

C/EBP homologous protein

CL:

Cardiolipin

Cryo-EM:

Cryomicroscopy

CSPα:

Cysteine string protein α

DLB:

Dementia with Lewy bodies

EMM:

External mitochondrial membrane

ENS:

Enteric nervous system

ERK:

Extracellular signal-regulated kinase

GC:

Golgi complex

HDAC6:

Histone deacetylase 6

HNE:

4-Hydroxy-2-nonenal

IF:

Intermediate filaments

IMM:

Internal mitochondrial membrane

LB:

Lewy bodies

LC3:

Microtubule-associated protein 1A/1B-light chain 3

LC3-II:

LC3-phosphatidylethanolamine conjugate

LN:

Lewy neurites

LP:

Lewy pathology

LRRK2:

Leucine-rich kinase 2

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

NF:

Neurofilaments

NMR:

Nuclear magnetic resonance

O-GlcNAc:

O-glycosyl-N-acetylation

PBD:

Protein Data Bank

PD:

Parkinson’s disease

RAB1A:

Ras-related protein Rab-1A

RER:

Rough endoplasmic reticulum

ROS:

Reactive oxygen species

SER:

Smooth endoplasmic reticulum

SNpc:

Substantia nigra pars compacta

SNAP-25:

Synaptosomal-associated protein 25

SNARE:

Soluble N-ethylmaleimide sensitive factor-attachment protein receptor

SUMO1:

Small ubiquitin-related modifier 1

TFEB:

Transcription factor EB

UPR:

Unfolded protein response

UPS:

Ubiquitine-proteasome system

VAMP2:

Vesicle associated membrane protein 2

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Acknowledgements

The authors appreciate the valuable support of Jorge Armando Florez-Ospina for artwork and M.Sci. Teresa Gómez-Quintero for references’ ordering.

Funding

This work was supported by grants R01ES03771 and R01ES10563 from the National Institute of Environmental Health Sciences (NIEHS) to MA.

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Author notes

  1. Iris N. Serratos, Elizabeth Hernández-Pérez, and Carolina Campos contributed equally to this work.

Authors and Affiliations

  1. Departamento de Química, Universidad Autónoma Metropolitana-Iztapalapa, 09340, Mexico City, Mexico

    Iris N. Serratos

  2. Departamento de Ciencias de La Salud, Universidad Autónoma Metropolitana-Iztapalapa, 09340, Mexico City, Mexico

    Elizabeth Hernández-Pérez & Carolina Campos

  3. Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, 10461, USA

    Michael Aschner

  4. Laboratorio de Aminoácidos Excitadores/Laboratorio de Neurofarmacología Molecular y Nanotecnología, Instituto Nacional de Neurología y Neurocirugía, SSA, 14269, Mexico City, Mexico

    Abel Santamaría

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  3. Carolina Campos
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  4. Michael Aschner
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Contributions

All authors contributed to the study conception and design. Material preparation, information collection, and analysis were performed by Iris N. Serratos, Elizabeth Hernández-Pérez, and Carolina Campos. All authors integrated information. The first draft of the manuscript was written by Iris N. Serratos, Elizabeth Hernández-Pérez, and Carolina Campos. Michael Aschner and Abel Santamaría translated, complemented, corrected, and edited the manuscript. All authors read and approved the final manuscript.

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Correspondence to Carolina Campos or Abel Santamaría.

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Highlights

1. α-Synuclein (α-Syn) plays important physiological roles in the brain

2. α-Syn is also involved in the pathogenesis of synucleinopathies

3. Conformational changes of α-Syn undergo post-translational modifications

4. Mutated α-Syn aberrantly interacts with membranes and organelles

5. Protein misfolding and aggregation trigger cellular dysfunction and pathology

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Serratos, I.N., Hernández-Pérez, E., Campos, C. et al. An Update on the Critical Role of α-Synuclein in Parkinson’s Disease and Other Synucleinopathies: from Tissue to Cellular and Molecular Levels. Mol Neurobiol 59, 620–642 (2022). https://doi.org/10.1007/s12035-021-02596-3

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