From synaptic development to degeneration: a narrative review of small molecule strategies targeting alpha-synuclein in Parkinson's disease.

Abstract

Aggregation of α-synuclein (α-Syn) is a defining pathological feature of Parkinson's disease (PD), contributing to progressive neuronal dysfunction and death. Unlike prior reviews focused predominantly on aggregation as an isolated endpoint, this review proposes a neurodevelopmental-neurodegenerative continuum as an interpretive framework, suggesting that α-Syn's physiological roles in synaptic development and circuit maturation may be linked to its later pathological behaviour. Within this context, we discuss recent advances in small-molecule strategies targeting key stages of α-Syn pathology, including synthesis, misfolding, aggregation, post-translational modification, and clearance. These include translation and misfolding inhibitors, aggregation modulators such as minzasolmin (UCB0599), epigallocatechin gallate and anle138b, as well as compounds that enhance α-Syn degradation through autophagy-lysosomal and ubiquitin-proteasome pathways. Additional strategies targeting proteostasis and mitochondrial dysfunction are also considered. Beyond its pathogenic role, α-Syn contributes to synaptic vesicle trafficking, neurotransmitter release, and neuronal maturation, and disruption of these functions may increase vulnerability to later neurodegeneration. In conclusion, small-molecule-based therapies represent a promising multi-targeted strategy for PD; however, key translational challenges and unresolved questions remain, including optimisation of pharmacokinetics, target specificity, and blood-brain barrier (BBB) penetration and validation in clinical settings.