bioRxiv : the preprint server for biology · 2026
A new therapeutic approach for Parkinson's disease: dual targeting of α-Synuclein aggregation and microglial function by the novel immunomodulator 3-Monothiopomalidomide.
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Palmas Maria Francesca, Aminzadeh Khosro, Runfola Matteo, Parekh Pathik, Porcedda Clara, Tweedie David, Casula Luca, Cardia Maria Cristina, Marongiu Jacopo, Etzi Michela, Lai Francesco, Serra Marcello, Pisanu Augusta, Sogos Valeria, De Simone Alfonso, Kim Dong Seok, Greig Nigel H, Carta Anna R
Аннотация
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.
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.