{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T18:16:30Z","timestamp":1775067390280,"version":"3.50.1"},"posted":{"date-parts":[[2026,3,30]]},"group-title":"Neuroscience","reference-count":63,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T00:00:00Z","timestamp":1774828800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"Intramural Research Program, National Institute on Aging, NIH, USA","award":["AG000994)"],"award-info":[{"award-number":["AG000994)"]}]},{"name":"MNESYS Spoke 7 (Neuroimmunology and Neuroinflammation): PROFILES, Funded by EU - Next Generation EU, Missione 4 Componente 2 investimento 1.3","award":["B33C22001060002"],"award-info":[{"award-number":["B33C22001060002"]}]},{"name":"PRIN 2022","award":["P20222F4JY"],"award-info":[{"award-number":["P20222F4JY"]}]},{"name":"Aevis Bio, Inc., Republic of Korea (the Korea Dementia Research Center (KDRC), funded by the Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea","award":["RS-2024-0034124913"],"award-info":[{"award-number":["RS-2024-0034124913"]}]},{"name":"the Korea Drug Development Fund funded by the Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare, Republic of Korea","award":["KDDF RS-2024-00338017"],"award-info":[{"award-number":["KDDF RS-2024-00338017"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\u03b1-Synuclein (\u03b1-Syn) plays a central role in Parkinson\u2019s disease (PD). Under pathological conditions, \u03b1-Syn aggregates into toxic oligomers and fibrils that act as damage-associated molecular patterns (DAMPs), stimulating microglial reactivity. This \u03b1-Syn\u2013microglia 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, \u03b1-Syn pathology spreads through the brain, disrupting synaptic plasticity in cognitive regions like the cortex and hippocampus, leading to early cognitive decline. Thus, targeting \u03b1-Syn aggregation and its inflammatory consequences presents a promising dual-hit therapeutic strategy for PD.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    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 \u03b1-Syn oligomers (H-\u03b1SynOs). 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\n                    <jats:italic>in vivo<\/jats:italic>\n                    in a rat model of PD induced by intracerebral infusion of H-\u03b1SynOs.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    In primary cell cultures, 3MP dose-dependently reduced \u03b1-Syn-induced neuronal death and microglial inflammatory responses. It also significantly inhibited \u03b1-Syn aggregation\n                    <jats:italic>in vitro<\/jats:italic>\n                    in the ThT assay and in SH-SY5Y cells exposed to \u03b1-Syn protofibrils, outperforming POM. When chronically administered\n                    <jats:italic>in vivo<\/jats:italic>\n                    , 3MP preserved dopaminergic neurons within the SNpc and yielded functional benefits on motor and cognitive readouts. Notably, 3MP markedly attenuated \u03b1-Syn aggregates induced by the H-\u03b1SynOs infusion in the SNpc more efficiently than POM, as shown by reduced intraneuronal staining for pSer129-\u03b1-Syn+ and reduced pSer129-\u03b1Syn in both cytoplasmic and phagolysosomal compartments of microglia. In addition, mesencephalic and cortical inflammatory microgliosis that followed to intranigral H-\u03b1SynOs-infusion, were significantly dampened by 3MP.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Overall, 3MP emerges as a dual-action drug candidate capable of modulating neuroinflammation and \u03b1-Syn aggregation and thereby disrupting the \u03b1-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.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.03.26.714051","type":"posted-content","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T18:50:13Z","timestamp":1774896613000},"source":"Crossref","is-referenced-by-count":0,"title":["A new therapeutic approach for Parkinson\u2019s disease: dual targeting of \u03b1-Synuclein aggregation and microglial function by the novel immunomodulator 3-Monothiopomalidomide"],"prefix":"10.64898","author":[{"given":"Maria Francesca","family":"Palmas","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Khosro","family":"Aminzadeh","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of 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