Sogos, V. | Search bioRxiv

bioRxiv2026

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

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.

neuroscience↗

bioRxiv2026

Corticospinal propagation of full-length TDP-43 toxicity drives brain-to-muscle pathology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of upper and lower motor neurons. Cytoplasmic inclusions containing TAR DNA-binding protein 43 (TDP-43), a key regulator of RNA metabolism, represent a pathological hallmark of all sporadic (sALS) and most familial (fALS) forms, underscoring its central role in disease pathophysiology. In affected neurons, full-length (FL) TDP-43 undergoes nuclear-to-cytoplasmic mislocalization, leading to aggregation and cellular dysfunction, and can be released to propagate pathology across neural and non-neural circuits. However, the in vivo toxicity and spreading capacity of FL TDP-43 remain poorly defined. Here, we show that purified, stable human FL TDP-43 was readily internalized by neuronal cells, where it induced aggregation and significantly reduced cell viability. In vivo, an acute unilateral stereotaxic infusion of FL TDP-43 into the rat primary motor cortex was sufficient to trigger a robust centrifugal propagation of pathology along the corticospinal axis and beyond the central nervous system (CNS). TDP-43 pathology spread from the motor cortex to the spinal cord and reached skeletal muscle. At the cellular level, propagated pathology was characterized by intraneuronal phosphorylated TDP-43 (pTDP-43) inclusions, accumulation of high-molecular-weight TDP-43 species, region-specific neurodegeneration, and pronounced mitochondrial vulnerability. Notably, skeletal muscle displayed impaired mitochondrial bioenergetics, accompanied by both motor and non-motor behavioral deficits. Collectively, our findings demonstrate neuron-to-neuron, brain-to-spinal cord and brain-to-muscle spreading of FL TDP-43 toxicity in vivo, establishing a mechanistic link between central TDP-43 pathology and peripheral dysfunction. This work identifies FL TDP-43 as an active driver of disease spreading in ALS and provides the basis for a non-transgenic, TDP-43-driven rat model of disease propagation.

neuroscience↗