Synucleins

Introduction

Synucleins are soluble proteins that include three well-known proteins, namely α-synuclein, β-synuclein, and γ-synuclein. The α- and β-synuclein proteins are found primarily in brain tissue. The γ-synuclein protein is found primarily in the peripheral nervous system and retina, but its expression in breast tumors is a marker for tumor progression. In disease, α-synuclein polymerizes into insoluble β-sheet-rich protein aggregates that become phosphorylated at residue Ser129 and deposit within the central nervous system (CNS). α-Synuclein is believed to play a central pathogenic role in the synucleinopathies, since mutations in the gene encoding α-synuclein cause early-onset Parkinson's disease, Alzheimer's disease, Lewy bodies and several other neurodegenerative illnesses. α-Synuclein participates the following neurotoxic pathways which ultimately lead to neurodegeneration.

• Autophagy-Lysosomal dysregulation
• Synaptic dysfunction
• Mitochondrial disruption
• Endoplasmic reticulum
• Oxidative stress

Fig.1 Diagram of the three human synucleins. (Pacheco, 2012)

Therapeutic Approaches Targeting α-Synuclein

At present, systematic strategies targeting α-synuclein include stabilizing the physiological conformation of α-synuclein, inhibiting its aggregation, decreasing its expression, increasing intracellular clearance, inhibiting uptake by neighboring cells and enhancing extracellular clearance mechanisms.

1. Reducing aggregation - Impeding the multimerization of α-synuclein through heat shock proteins (HSPs) or by dissociating existing aggregates
2. Reducing expression - Modulating histone deacetylase or through RNA interference (RNAi) strategies
3. Blocking α-synuclein entry - Receptor blocking
4. Neutralize α-synuclein extracellularly or even intracellularly in the case of single domain antibodies

Fig.2 Therapeutic strategies targeting α-synuclein. (Fields, 2019)

Future Directions

Much work remains to be done:

• Illustrate the normal cellular functions of these unusually conserved proteins.
• Determine how they contribute to diverse disease processes spanning neurodegenerative disease and cancer.

Several pre-clinical therapeutic modalities targeting pathological α-synuclein have revealed promising results. These approaches include treatments designed to inhibit the synthesis, aggregation, or uptake of abnormal α-synuclein and enhance extracellular protein clearance mechanisms. α-Synuclein immunotherapies have gained significant interest as potential methods that might slow or halt the progression of the disease. It’s provided that targeting toxic α-synuclein seem to be a compelling strategy for therapeutic targets in neurodegenerative illnesses. For any customized services or products, please feel free to contact us for cooperation.

References

1. Pacheco, C.; et al. An extracellular mechanism that can explain the neurotoxic effects of α-synuclein aggregates in the brain. Frontiers in physiology. 2012, 3: 297.
2. Fields, C. R.;et al. Targeting alpha-synuclein as a therapy for Parkinson’s disease.Frontiers in molecular neuroscience. 2019, 12: 299.