Abstract
BACKGROUND: α-Synuclein (α-Syn) plays a central role in Parkinson's disease (PD). Under pathological conditions, α-Syn aggregates into toxic oligomers and fibrils that act as damage-associated molecular patterns (DAMPs), stimulating microglial reactivity. This α-Syn-microglia axis creates a self-perpetuating cycle of neuroinflammation and neurodegeneration, accelerating dopaminergic neuron loss in the substantia nigra pars compacta (SNpc) and contributing to motor deficits. Moreover, α-Syn pathology spreads through the brain, disrupting synaptic plasticity in cognitive regions like the cortex and hippocampus, leading to early cognitive decline. Thus, targeting α-Syn aggregation and its inflammatory consequences presents a promising dual-hit therapeutic strategy for PD. METHODS: This study investigates the therapeutic potential of 3-monothiopomalidomide (3MP), a novel thalidomide derivative designed to reduce neuroinflammation with a potentially better safety profile than Pomalidomide (POM). The neuroprotective and anti-inflammatory effects of 3MP were evaluated in rat primary mesencephalic mixed neuron-microglia cultures exposed to human α-Syn oligomers (H-αSynOs). Anti-aggregation activity was assessed via Thioflavin T (ThT) assays and Thioflavin S (ThS) staining in SH-SY5Y cells. Finally, the anti-aggregation, anti-inflammatory, and neuroprotective effects of 3MP were evaluated in vivo in a rat model of PD induced by intracerebral infusion of H-αSynOs. RESULTS: In primary cell cultures, 3MP dose-dependently reduced α-Syn-induced neuronal death and microglial inflammatory responses. It also significantly inhibited α-Syn aggregation in vitro in the ThT assay and in SH-SY5Y cells exposed to α-Syn protofibrils, outperforming POM. When chronically administered in vivo , 3MP preserved dopaminergic neurons within the SNpc and yielded functional benefits on motor and cognitive readouts. Notably, 3MP markedly attenuated α-Syn aggregates induced by the H-αSynOs infusion in the SNpc more efficiently than POM, as shown by reduced intraneuronal staining for pSer129-α-Syn+ and reduced pSer129-αSyn in both cytoplasmic and phagolysosomal compartments of microglia. In addition, mesencephalic and cortical inflammatory microgliosis that followed to intranigral H-αSynOs-infusion, were significantly dampened by 3MP. CONCLUSIONS: Overall, 3MP emerges as a dual-action drug candidate capable of modulating neuroinflammation and α-Syn aggregation and thereby disrupting the α-Syn-driven inflammatory cycle. Its neuroprotective effects and favourable safety profile support its potential as a disease-modifying therapy for PD, with promising implications for clinical translation.