α-Synuclein Pathology in Synucleinopathies: Mechanisms, Biomarkers, and Therapeutic Challenges
Abstract
1. Introduction
2. Physiological α-Synuclein: A Necessary Disordered Protein
2.1. Structure of α-Synuclein
2.2. Function and Subcellular Localization of α-Synuclein
2.3. α-Synuclein Interactome Further Complexes Its Understanding
2.4. Mechanisms of α-Synuclein Clearance
3. Mechanisms of Aggregation and Pathology
3.1. Mechanisms of Aggregation
3.2. Role of Post-Translational Modifications and Metals in α-Synuclein Pathology
3.3. Lewy Bodies and Pathological Inclusions
3.4. Genetic and Phenotypic Diversity in Synucleinopathies
4. Propagation and Spreading
4.1. The Role of α-Synuclein Spreading in Pathology
4.2. Immune Responses and the Microbiome in Parkinson’s Disease Pathogenesis
5. Models of Synucleinopathies
5.1. Animal Models of Synucleinopathies Through α-Synuclein Expression
5.2. Cellular Models of α-Synuclein Toxicity and Aggregation
6. Towards Diagnostic and Therapeutic Strategies
6.1. Biomarkers for Diagnosis
6.2. Therapeutic Strategies
7. Discussion
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
BBB | Blood–Brain Barrier |
CMA | Chaperone-Mediated Autophagy |
CNS | Central Nervous System |
CRISPR | Clustered Regularly Interspaced Short Palindromic Repeats |
CSF | Cerebrospinal Fluid |
DLB | Dementia with Lewy Bodies |
ER | Endoplasmic Reticulum |
GBA1 | Glucocerebrosidase Beta 1 |
GCIs | Glial Cytoplasmic Inclusions |
GWAS | Genome-Wide Association Study |
IDP | Intrinsically Disordered Protein |
LB | Lewy Body |
LRRK2 | Leucine-Rich Repeat Kinase 2 |
MAMs | Mitochondria-Associated Membranes |
MRI | Magnetic Resonance Imaging |
MSA | Multiple System Atrophy |
NAC | Non-Amyloid Component |
NMR | Nuclear Magnetic Resonance |
PD | Parkinson’s Disease |
PET | Positron Emission Tomography |
PMCA | Protein Misfolding Cyclic Amplification |
PrPC | Cellular Prion Protein |
RT-QuiC | Real-Time Quaking-Induced Conversion |
SAA | Seed Amplification Assay |
SN | Substantia Nigra |
UPS | Ubiquitin–Proteasome System |
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Arias-Carrión, O.; Guerra-Crespo, M.; Padilla-Godínez, F.J.; Soto-Rojas, L.O.; Manjarrez, E. α-Synuclein Pathology in Synucleinopathies: Mechanisms, Biomarkers, and Therapeutic Challenges. Int. J. Mol. Sci. 2025, 26, 5405. https://doi.org/10.3390/ijms26115405
Arias-Carrión O, Guerra-Crespo M, Padilla-Godínez FJ, Soto-Rojas LO, Manjarrez E. α-Synuclein Pathology in Synucleinopathies: Mechanisms, Biomarkers, and Therapeutic Challenges. International Journal of Molecular Sciences. 2025; 26(11):5405. https://doi.org/10.3390/ijms26115405
Chicago/Turabian StyleArias-Carrión, Oscar, Magdalena Guerra-Crespo, Francisco J. Padilla-Godínez, Luis O. Soto-Rojas, and Elías Manjarrez. 2025. "α-Synuclein Pathology in Synucleinopathies: Mechanisms, Biomarkers, and Therapeutic Challenges" International Journal of Molecular Sciences 26, no. 11: 5405. https://doi.org/10.3390/ijms26115405
APA StyleArias-Carrión, O., Guerra-Crespo, M., Padilla-Godínez, F. J., Soto-Rojas, L. O., & Manjarrez, E. (2025). α-Synuclein Pathology in Synucleinopathies: Mechanisms, Biomarkers, and Therapeutic Challenges. International Journal of Molecular Sciences, 26(11), 5405. https://doi.org/10.3390/ijms26115405