Biology subjects

Weiss, F. D.

Publications and source records attributed to Weiss, F. D..

4 recordsLinked to original sources

bioRxiv2025

NLRP3 inhibition maintains microglia architecture and enhances behavioral recovery after traumatic brain injury

NLRP3 plays an essential role in secondary neuroinflammatory damage following traumatic brain injury (TBI). However, the specific mechanisms mediating NLRP3s effects in TBI remain poorly understood, and it is unknown whether its pharmacological inhibition with oral compounds during initial phases confers long-term protection. In this study, we investigated the role of the NLRP3 inflammasome pathway in TBI-induced neuroinflammation and long-term neurobehavioral impairment, as well as the impact of its pharmacological inhibition. Following controlled cortical impact (CCI), most NLRP3 inflammasome-related proteins and key inflammatory markers were elevated during the first week post-injury. Genetic Nlrp3 deletion and treatment with oral NLRP3-specific inhibitors preserved microglial homeostatic architecture, reduced ASC aggregation, and enhanced neurological and cognitive recovery after CCI. Repeated intravital imaging confirmed that NLRP3 inhibition prevents microglial activation post-TBI. These findings suggest NLRP3 inflammasome targeting represents a viable translational strategy for clinical trials and may mitigate long-term neurocognitive decline following TBI.

neuroscience↗

bioRxiv2024

Retention of ES cell-derived 129S genome drives NLRP1 hypersensitivity and transcriptional deregulation in Nlrp3-/- mice

Immune response genes are highly polymorphic in humans and mice, with heterogeneity amongst loci driving strain-specific host defense responses. The inadvertent retention of polymorphic loci can introduce confounding phenotypes, leading to erroneous conclusions, and impeding scientific advancement. In this study, we employ a combination of RNAseq and variant calling analyses and identify a substantial region of 129S genome, including the highly polymorphic Nlrp1 locus proximal to Nlrp3, in one of the most commonly used mouse models of NLRP3 deficiency. We show that increased expression of 129S NLRP1b sensitizes Nlrp3-/- macrophages to NLRP1 inflammasome activation. Furthermore, the presence of 129S genome leads to altered gene and protein regulation across multiple cell-types, including of the key tissue-resident macrophage marker, TIM4. To address the challenge of resolving NLRP3-dependent phenotypes, we introduce and validate a conditional Nlrp3 allele, enabling precise temporal and cell-type-specific control over Nlrp3 deletion. Our study establishes a generic framework to identify functionally relevant SNPs and assess genomic contamination in transgenic mice. This allows for unambiguous attribution of phenotypes to the target gene and advances the precision and reliability of research in the field of host defense responses.

immunology↗

bioRxiv2021

Activity-induced gene expression and long-range enhancer-promoter contacts in cohesin-deficient neurons

Cohesin and CTCF are major drivers of 3D genome organization, but their role in neurons is still emerging. Here we show a prominent role for cohesin in the expression of genes that facilitate neuronal maturation and homeostasis. Unexpectedly, we observed two major classes of activity-regulated genes with distinct reliance on cohesin in primary cortical neurons. Immediate early genes remained fully inducible by KCl and BDNF, and short-range enhancer-promoter contacts at the Immediate early gene Fos formed robustly in the absence of cohesin. In contrast, cohesin was required for full expression of a subset of secondary response genes characterised by long-range chromatin contacts. Cohesin-dependence of constitutive neuronal genes with key functions in synaptic transmission and neurotransmitter signaling also scaled with chromatin loop length. Our data demonstrate that key genes required for the maturation and activation of primary cortical neurons depend cohesin for their full expression, and that the degree to which these genes rely on cohesin scales with the genomic distance traversed by their chromatin contacts.

genomics↗

bioRxiv2020

Partial rescue of neuronal genes deregulated in Cornelia de Lange Syndrome by cohesin

Cornelia de Lange Syndrome (CdLS) is a human developmental disorder caused by mutations that compromise the function of cohesin, a major regulator of 3D genome organization. Cognitive impairment is a universal and as yet unexplained feature of CdLS. We characterized the transcriptional profile of cortical neurons from CdLS patients and found deregulation of hundreds of genes enriched for neuronal functions related to synaptic transmission, signalling processes, learning and behaviour. Inducible proteolytic cleavage of cohesin disrupted 3-D genome organization and transcriptional control in post-mitotic cortical mouse neurons. The genes affected belonged to similar gene ontology classes and showed significant numerical overlap with those deregulated in CdLS. Interestingly, gene expression was largely rescued by subsequent reconstitution of cohesin function. These experiments show that cohesin is continuously required for neuronal gene expression and provide a tractable approach for addressing mechanisms of neuronal dysfunction in CdLS.

cell biology↗