Alpha-synuclein Targeting Therapies Study

Normal alpha-synuclein (α-syn) plays an essential role in brain cell communication, and growing evidence indicates that toxic forms of α-syn are closely related to Parkinson's disease (PD). Therefore, there is great interest in targeting α-syn to block the progression of PD. As a renowned innovative biotechnology company, Creative Biolabs has extensive experience in neuroscience research. With our advanced platform and extensive expertise, we are committed to developing custom animal models and suitable approaches to help you further understand the mechanism of action (MoA) of α-syn in PD.

α-syn and PD

PD is one of the most common neurodegenerative diseases worldwide. However, there is no effective way to prevent or treat PD at present. It is worth noting that increasing evidence showed that elevated α-syn protein levels were responsible for the pathogenesis of PD. α-syn is an abundant 14 kDa protein, encoded by the SNCA gene, consisting of 140 amino acids. α-syn consists of three domains: an N-terminal lipid-binding α-helix, a non-amyloid component (NAC), and an acidic C-terminal tail. Aggregation of α-syn and accumulation in cytoplasmic inclusions called Lewy bodies are pathological hallmarks of PD, revealing that α-syn plays a central role in the pathogenesis of PD.

Therapeutic Strategies Targeting α-Syn for PD

To date, α-syn is one of the most promising targets for PD. There are various approaches to treating disease by targeting the diffusion, production, aggregation, and increased intracellular clearance of α-syn. In addition, manipulation of SNCA levels has shown beneficial effects.

Fig.1 Therapeutic strategies targeting α-Syn for PD treatment. (Fields, et al., 2019)

• Decreasing the expression of α-syn

Reducing α-syn expression affects the amount of α-Syn protein available for aggregation and pathway disruption. Studies have shown that manipulation of α-syn levels through gene silencing and RNA interference is beneficial for normalizing α-syn expression and improving motor function. Furthermore, DNA methylation of SNCA intron 1 is a regulator of α-syn transcription, and methylation levels are different in PD compared to controls, thus providing a target for tight control of α-syn expression levels.

• Prevention of α-syn aggregation

Targeting α-syn aggregation using specific molecules is an attractive strategy. Various compounds proved to be effective in inhibiting α-syn aggregation in PD. For example, heat shock proteins (HSPs) prevent protein aggregation and toxicity under conditions of cellular stress. Manipulation of the expression of HSPs in vitro and in vivo models is critical in regulating α-syn aggregation and toxicity. Furthermore, several lines of evidence suggest that various novel oligomer modulators are effective in inhibiting oligomer formation in mouse models of PD.

• Immunotherapies targeting α-syn

The development of vaccines targeting the N or C-terminus of α-syn or its aggregated forms is an active immunization approach. It was reported that various α-syn mimetic peptides have shown good safety and efficacy in PD. What's more, long-term intravenous administration of the antibody will prevent the formation and spread of pathogenic α-syn aggregates and may alter disease progression.

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Reference

1. Fields, C.R.; et al. Targeting alpha-synuclein as a therapy for Parkinson's disease. Frontiers in molecular neuroscience. 2019, 12: 299.