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bioRxiv · 10.64898/2026.03.26.714051

A new therapeutic approach for Parkinson's disease: dual targeting of alpha-Synuclein aggregation and microglial function by the novel immunomodulator 3-Monothiopomalidomide

Palmas, M. F.·Aminzadeh, K.·Runfola, M.·Parekh, P.·Porcedda, C.·Tweedie, D.·Casula, L.·Cardia, M. C.·Marongiu, J.·Etzi, M.·Lai, F.·Serra, M.·Pisanu, A.·Sogos, V.·De Simone, A.·Kim, D. S.·Greig, N. H.·Carta, A. R.
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Abstract

Background-Synuclein (-Syn) plays a central role in Parkinsons disease (PD). Under pathological conditions, -Syn aggregates into toxic oligomers and fibrils that act as damage-associated molecular patterns (DAMPs), stimulating microglial reactivity. This -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, -Syn pathology spreads through the brain, disrupting synaptic plasticity in cognitive regions like the cortex and hippocampus, leading to early cognitive decline. Thus, targeting -Syn aggregation and its inflammatory consequences presents a promising dual-hit therapeutic strategy for PD. MethodsThis 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 -Syn oligomers (H-SynOs). 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-SynOs. ResultsIn primary cell cultures, 3MP dose-dependently reduced -Syn-induced neuronal death and microglial inflammatory responses. It also significantly inhibited -Syn aggregation in vitro in the ThT assay and in SH-SY5Y cells exposed to -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 -Syn aggregates induced by the H-SynOs infusion in the SNpc more efficiently than POM, as shown by reduced intraneuronal staining for pSer129--Syn+ and reduced pSer129-Syn in both cytoplasmic and phagolysosomal compartments of microglia. In addition, mesencephalic and cortical inflammatory microgliosis that followed to intranigral H-SynOs-infusion, were significantly dampened by 3MP. ConclusionsOverall, 3MP emerges as a dual-action drug candidate capable of modulating neuroinflammation and -Syn aggregation and thereby disrupting the -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.

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Palmas, M. F., Aminzadeh, K., Runfola, M., Parekh, P., Porcedda, C., Tweedie, D., Casula, L., Cardia, M. C., Marongiu, J., Etzi, M., Lai, F., Serra, M., Pisanu, A., Sogos, V., De Simone, A., Kim, D. S., Greig, N. H., Carta, A. R.. 2026-03-30. A new therapeutic approach for Parkinson's disease: dual targeting of alpha-Synuclein aggregation and microglial function by the novel immunomodulator 3-Monothiopomalidomide. https://doi.org/10.64898/2026.03.26.714051

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