Biology subjects

Ferreira, S. A.

Publications and source records attributed to Ferreira, S. A..

6 recordsLinked to original sources

bioRxiv2025

Lack of functional STING modulates immunity but does not protect dopaminergic neurons in the alpha-synuclein preformed fibrils Parkinson's Disease mouse model

Microglia response is proposed to be relevant in the neurogenerative process associated with alpha-synuclein (-syn) pathology in Parkinsons disease (PD). STING is a protein related to the immune sensing of DNA and autophagy, and it has been proposed to be involved in PD neurodegeneration. To investigate this, we injected 10 {micro}g of murine pre-formed fibrils (PFFs) of -syn (or monomeric and PBS as controls) into the striatum of wild-type (WT) and STINGgt/gt mice, which lack functional STING. We examined motor behavior and brain pathology at 1- and 6-months post-injection. STINGgt/gt mice showed more motor changes associated with PFF injection than WT mice. STINGgt/gt mice had a differential immune response to PFF with early and sustained increased microglia numbers and higher macrophagic CD68 response, but milder changes in the expression of immune-relevant markers such as TLR2, TLR4, IL1b, and TREM2. However, the lack of STING did not induce changes in the extent of -syn pathology nor the p62 accumulation seen in the model. Altogether, this resulted in a faster but similar degree of nigrostriatal dopaminergic degeneration after 6 months. Therefore, the data do not support a necessary role for STING in the -syn induced nigral neuronal loss in the PFF-PD mouse model used here. However, the results suggest a functional relevance for STING in the brain response to the excess and aggregation of amylogenic proteins such as -syn that can contribute to symptomatic changes.

neuroscience↗

bioRxiv2025

Biodiversity State Indicator: Integrating taxonomy, functionality and species interactions

The biodiversity crisis is a pressing global issue, mainly driven by climate change and anthropogenic pressures. Efforts to mitigate climate change have had limited success, emphasizing the need to address local stressors to prevent biodiversity collapse. However, measuring biodiversity remains complex due to its multifaceted nature, including taxonomic, functional, and interaction dimensions. This study introduces the Biodiversity State Indicator (BSI), an integrated metric designed to assess biodiversity by combining classic taxonomic biodiversity with functional biodiversity and community interactions. The BSI calculates the state of biodiversity at a target site, compared to reference ecosystems, enabling the indicator to assess net-positive or net-negative biodiversity change. The indicator is validated through simulations and applied to North Sea data, demonstrating its sensitivity to species richness and its capacity to track biodiversity changes over time. The BSI was shown to perform accordingly to expectation, showing no preference for a specific metric included in the calculations. Additionally, the BSI showed that while giving a clear and simple number to communicate and relate state of biodiversity and biodiversity changes, resolving the calculations into its constituent components can assist in resolving some of the internal ecosystem dynamics by levering changes in taxonomic, functional and interaction diversity with each other. In conclusion, the Biodiversity State Indicator can be a solid tool to assist in the net-positive strategy of marine stakeholders, developers and decision makers.

ecology↗

bioRxiv2024

Peripherally administered TNF inhibitor is not protective against α-synuclein-induced dopaminergic neuronal death in rats

The underlying cause of neuronal loss in Parkinsons disease (PD) remains unknown, but evidence implicates neuroinflammation in PD pathobiology. The pro-inflammatory cytokine soluble tumor necrosis factor (TNF) seems to play an important role and thus has been proposed as a therapeutic target for modulation of the neuroinflammatory processes in PD. In this regard, dominant-negative TNF (DN-TNF) agents are promising antagonists that selectively inhibit soluble TNF signaling, while preserving the beneficial effects of transmembrane TNF. Previous studies have tested the protective potential of DN-TNF-based therapy in toxin-based PD models. Here we test for the first time the protective potential of a DN-TNF therapeutic against -synuclein-driven neurodegeneration in the viral vector-based PD rat model. To do so, we administered the DN-TNF agent XPro1595 subcutaneously for a period of 12 weeks. In contrast to previous studies using different PD models, neuroprotection was not achieved by systemic XPro1595 treatment. -synuclein-induced loss of nigrostriatal neurons, accumulation of pathological inclusions and microgliosis was detected in both XPro1595- and saline-treated animals. XPro1595 treatment increased the percentage of the hypertrophic/ameboid Iba1+ cells in SN and reduced the striatal MHCII+ microglia in the striatum of -synuclein-overexpressing animals. However, the treatment did not prevent the MHCII upregulation seen in the SN of the model, nor the increase of CD68+ phagocytic cells. Therefore, despite an apparently positive immune effect, this did not suffice to protect against viral vector-derived -synuclein-induced neurotoxicity. Further studies are warranted to better elucidate the therapeutic potential of soluble TNF inhibitors in PD.

neuroscience↗

bioRxiv2024

Molecular signatures of altered energy metabolism and circadian rhythm perturbations in a model of extra-nigral Synucleinopathy.

A pathological role of alpha-Synuclein (aSyn) aggregation in the central nervous system (CNS) is a recognized feature in Parkinson disease (PD) and related neurodegenerative conditions termed synucleinopathies. In order to characterize the cellular response in CNS to incipient and advanced aSyn pathology, we applied spatial transcriptomics on brain sections derived from a transgenic mouse model (M83+/+ line, Prnp-SNCA*A53T) in which aSyn aggregation was induced in a prion-like fashion through hindlimb intramuscular delivery of pre-formed fibrillar (PFF) murine aSyn. Our spatially-resolved transcriptomics (ST) data point to unique perturbations in brain energy metabolism during the progression of aSyn pathology, such that the early stage of aSyn aggregate pathology activates molecular pathways controlling metabolic flux through glycolysis, oxidative phosphorylation and fatty acid metabolism. In contrast, the ST data indicate a profound decline in mitochondrial metabolism in the brains of symptomatic animals with advanced aSyn pathology. The latter stage was also associated with drastic reduction in mRNA translation machinery, along with aberrant expression of molecular drivers involved in RNA splicing and inflammatory response. Intriguingly, our ST data also point to perturbed regulation of circadian rhythm, was corroborated by increased immunodetection of CREB-binding protein (a modulator of core clock machinery) in the brains of symptomatic animals, and transcriptional upregulation of CREBBP in 4 independent PD microarray datasets. Collectively, we anticipate that our findings offer novel opportunities in knowledge translation for mechanism-based drug discovery and biomarkers in neurodegenerative synucleinopathies.

neuroscience↗

bioRxiv2024

Bradykinesia and postural instability in a model of prodromal Synucleinopathy with alpha-Synuclein aggregation in the gigantocellular nuclei.

-Synuclein (aSyn) accumulation within the extra-nigral neuronal populations in brainstem, including the gigantocellular nuclei (GRN/Gi) of reticular formation, is a recognized feature during the prodromal phase of Parkinson disease (PD). Accordingly, there is a burgeoning interest in animal model development for understanding the pathological significance of extra-nigral synucleinopathy, in relation to motor and/or non-motor symptomatology in PD. Here, we report an experimental paradigm for the induction of aSyn aggregation in brainstem, with stereotaxic delivery of pre-formed fibrillar (PFF) aSyn in the pontine GRN of transgenic mice expressing the mutant human Ala53Thr aSyn (M83 line). Our data show that PFF aSyn-induced aggregate pathology in GRN leads to progressive decline in spontaneous locomotion and an early phenotype of postural instability. This early phase of bradykinesia was followed by a moribund stage, characterized by worsening motor performance and impaired survival with substantial aSyn aggregation in several brain regions beyond the GRN. Collectively, our observations suggest an experimental framework for studying the pathological significance of aSyn aggregation in GRN in relation to features of movement disability in PD. With further refinements, we anticipate that this model holds promise as a test-bed for translational research in PD and related disorders.

neuroscience↗

bioRxiv2022

Sex-dimorphic neuroprotective effect of CD163 in an alpha-synuclein mouse model Of Parkinson's disease

Alpha-synuclein (-syn) aggregation and immune activation represent hallmark pathological events in Parkinsons disease (PD). The PD-associated immune response encompasses both brain and peripheral immune cells, although little is known about the immune proteins relevant for such response. We propose that the upregulation of CD163 observed in blood monocytes and in the responsive microglia in the PD patients is a protective mechanism in the disease. To investigate this, we used the PD model based on intrastriatal injections of murine -syn pre-formed fibrils (PFF) in CD163 knockout (KO) mice and wild-type littermates. CD163KO females revealed an impaired and differential early immune response to -syn pathology as revealed by immunohistochemical and transcriptomic analysis. After 6 months, CD163KO females showed an exacerbated immune response and -syn pathology, which ultimately led to dopaminergic neurodegeneration of greater magnitude. These findings support a novel, sex-dimorphic neuroprotective role for CD163 during -syn-induced neurodegeneration.

neuroscience↗