Biology subjects

Carta, A. R.

Publications and source records attributed to Carta, A. R..

3 recordsLinked to original sources

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↗

bioRxiv2018

Modulation of ERK1/MAPK3 potentiates ERK nuclear signalling, facilitates neuronal cell survival and improves memory in mouse models of neurodegenerative disorders

Cell signalling mechanisms are central to neuronal activity and their dysregulation may lead to neurodegenerative processes and associated cognitive decline. So far, a major effort has been directed toward the dissection of disease specific pathways with the still unmet promise to develop precision medicine strategies. With a different approach, here we show that a selective genetic potentiation of neuronal ERK signalling prevents cell death in vitro and in vivo in the mouse brain while ERK attenuation does the opposite. This neuroprotective effect can also be induced pharmacologically by a cell permeable peptide mimicking the loss of ERK1 MAP kinase, leading to a selective enhancement of ERK2 mediated nuclear cell signalling. The drug treatment prevents neurodegeneration in mouse models of Huntingtons (HD), Alzheimers (AD), and Parkinsons disease (PD). Importantly, the selective potentiation of ERK2 signalling facilitates both structural and synaptic plasticity, enhances cognition in healthy mice and rescues mild cognitive impairments in both models of AD and HD. Altogether, our observation truly represents a remarkable example of a shared molecular mechanism across multiple neurodegenerative disorders and a potentially valuable therapeutic target for neuro-enhancement.

neuroscience↗