Novel Therapeutic Horizons: SNCA Targeting in Parkinson's Disease

Abstract

Alpha-synuclein (αSyn) aggregates are the primary component of Lewy bodies, which are pathological hallmarks of Parkinson's disease (PD). The toxicity of αSyn seems to increase with its elevated expression during injury, suggesting that therapeutic approaches focused on reducing αSyn burden in neurons could be beneficial. Additionally, studies have shown higher levels of SNCA mRNA in the midbrain tissues and substantia nigra dopaminergic neurons of sporadic PD post-mortem brains compared to controls. Therefore, the regulation of SNCA expression and inhibition of αSyn synthesis could play an important role in the pathogenesis of injury, resulting in an effective treatment approach for PD. In this context, we summarized the most recent and innovative strategies proposed that exploit the targeting of SNCA to regulate translation and efficiently knock down cytoplasmatic levels of αSyn. Significant progress has been made in developing antisense technologies for treating PD in recent years, with a focus on antisense oligonucleotides and short-interfering RNAs, which achieve high specificity towards the desired target. To provide a more exhaustive picture of this research field, we also reported less common but highly innovative strategies, including small molecules, designed to specifically bind 5'-untranslated regions and, targeting secondary nucleic acid structures present in the SNCA gene, whose formation can be modulated, acting as a transcription and translation control. To fully describe the efficiency of the reported strategies, the effect of αSyn reduction on cellular viability and dopamine homeostasis was also considered.

Keywords: ASOs; G-quadruplex; Parkinson’s disease; SNCA gene; alpha-synuclein; gene therapy.

Figure 1

Common chemical modifications to improve classical ASO features.

Figure 2

Chemical structure of AmNA and LNA phosphorothioate moieties.

Figure 3

siRNA pathway: ribonuclease protein Dicer recognizes and cleaves DNA double-strand into small fragments (21–23 bp), known as siRNAs, which form the protein RISC complex. Then, siRNA binds the target sequence on mRNA, inducing its cleavage into small fragments (10–11 bp). This results in the suppression of mRNA translation.

Figure 4

Chemical structures of ligands targeting 5′-UTR of SNCA mRNA.

Figure 5

Schematic representation of (A) square-planar G-tetrad; (B) backbone of the intramolecular G-quadruplex structure; (C) G4 topologies: parallel-, antiparallel-, and hybrid-type G4 structures.

Figure 6

Cartoon representing the three G4 motifs identified in the 5′-UTR mRNA region of the SNCA gene by Koukouraki et al. [78], together with all the G to A mutations tested (highlighted in yellow).