Biology subjects

Camera, M.

Publications and source records attributed to Camera, M..

6 recordsLinked to original sources

bioRxiv2026

Chronic Proliferation and Glia Heterogeneity in CMT1A: Involvement of RUNX2-Positive Schwann Cells and Endoneurial Fibroblasts

Charcot Marie Tooth type 1A (CMT1A) is the most common inherited peripheral neuropathy, caused by duplication of the peripheral myelin protein 22 (PMP22) gene and characterized by dysmyelination and defects in myelin maturation. Hypercellularity is a prominent feature of the disease, although its origin, persistence, and underlying mechanisms remain controversial. Here, we performed a longitudinal analysis of sciatic nerves from wild-type (WT) and CMT1A rats between 2 and 12 months of age. We demonstrated that CMT1A nerves exhibit persistent cellular proliferation extending into adulthood. This phenotype is confirmed by bulk RNA-seq data showing sustained enrichment of proliferation-associated gene signatures. Cell type signature analysis identifies overrepresentation of immature, neural crest related, and epithelial mesenchymal transitional (EMT) transcriptional programs in CMT1A nerves. Among the most upregulated genes, RUNX2 showed strong and prolonged expression at both transcript and protein levels. Consistently with the key role of RUNX2 in the activation of the injury response, CMT1A nerves also showed a marked enrichment in SOX10+JUN+ cells, that only partially overlap with SOX10+RUNX2+ cells, indicating a maladaptive activation of the injury-like Schwann cell (SC) program. Interestingly, we detected robust upregulation of SMOC2, an extracellular matrix protein selectively expressed by endoneurial fibroblasts, pointing to activation of non-canonical cell types and altered extracellular matrix remodeling. Together, these data demonstrate that CMT1A peripheral nerves are characterized by chronic hypercellularity driven by persistent proliferation, EMT, and dysregulated injury transcriptional programs, collectively pointing at progressive and multicellular nerve remodeling as a relevant pathomechanism in the disease.

neuroscience↗

bioRxiv2026

Lysergic acid diethylamide reverses aging- and neurodegeneration-associated brain transcriptional programs

Psychedelic compounds such as lysergic acid diethylamide (LSD) are increasingly studied for their neuroplastic effects and potential relevance to brain aging and neurodegeneration. However, the molecular mechanisms linking psychedelic-induced plasticity to age-associated cognitive decline remain unclear. Brain aging and dementia are characterized by coordinated transcriptional programs that underlie synaptic dysfunction and altered neuron-glia interactions. If psychedelic-induced plasticity engages opposing molecular programs, it could counteract these conserved trajectories. In computational drug discovery, this concept has been formalized as the principle of transcriptional signature reversal, whereby compounds inducing gene expression states opposite to disease-associated programs may exert a therapeutic effect by counteracting disease-associated phenotypes. Here, we combine cross-species transcriptomic analyses with experimental validation to test whether LSD opposes conserved signatures of brain aging and dementia. By comparing transcriptional profiles induced by chronic LSD treatment in rodents with age- and dementia-associated gene expression changes in the human prefrontal cortex, we show that LSD induces gene expression patterns strongly anti-correlated with aging and neurodegeneration programs. This reversal is specific compared to other pharmacological perturbations and is reproducible across datasets and species. Moreover, LSD counteracts amyloid-{beta}-induced structural and molecular alterations in primary cortical neurons, linking transcriptomic opposition to functional rescue under neurodegenerative stress. Together, our findings suggest that LSD modulates molecular and cellular pathways associated with brain aging and neurodegeneration, linking systems-level gene expression changes to structural and functional resilience in neurodegeneration-relevant contexts.

neuroscience↗

bioRxiv2026

ARHGEF6-dependent cytoskeletal regulation underlies a conserved program of forebrain interneuron development

The molecular programs coordinating inhibitory interneuron migration, maturation, and survival during forebrain development remain incompletely understood. Here we investigate ARHGEF6, a RAC1/CDC42 guanine nucleotide exchange factor linked to X-linked intellectual disability (XLID46) and previously studied only at postsynaptic compartments, and reveal an earlier, conserved role in forebrain interneuron development. ARHGEF6 is selectively enriched in the inhibitory lineage during the peak of interneuron generation and migration. Its loss in mice reduces the number of cortical and hippocampal interneurons, disrupts tangential migration, increases developmental cell death, and impairs morphological and electrophysiological maturation. Strikingly, ARHGEF6-knockout human iPSC-derived organoids and assembloids mirror these deficits exhibiting increased apoptosis, reduced neuronal output, disorganized growth cones, impaired neurite branching, and disrupted migratory dynamics. These cross-species findings reframe ARHGEF6 as an early, essential orchestrator of inhibitory circuit assembly and reveal a conserved cytoskeletal program whose disruption produces the excitatory-inhibitory imbalance linked to cognitive dysfunction.

developmental biology↗

bioRxiv2024

A sequential event-responsive fluorescent reporter for inducible Cre and Flp combinatorial recombination

Current technologies for precise genetic manipulation of cells often utilize site-specific recombinases, enabling the creation of conditional transgenic models for studying gene functions in specific tissues and at defined time windows. The advent of drug-inducible recombinases has further enhanced this field by allowing temporal control of gene expression. However, detecting gene expression patterns when multiple recombinases are used is challenging, particularly when visualizing combinatorial maps and their temporal profile. To address this, we developed Rubik, a fluorescent genetic reporter specifically designed to monitor the action of Cre and Flp recombinases by expressing different fluorophores depending on the temporal sequence of recombination events. Rubik offers four alternative fluorescent configurations: blue for Cre recombination, green for Flp recombination, yellow for Cre followed by Flp recombination, and red for Flp followed by Cre recombination. Additionally, Rubik integrates light-gated ion channels, allowing optogenetic excitation or inhibition of electrically-excitable cells based on the temporal sequence of recombination events. Moreover, to add temporal control over Rubik recombination, we optimized a trimethoprim-inducible FlpO recombinase (FlpO-DD) to use in combination with the tamoxifen-inducible Cre recombinase (ERT2CreERT2). We validated Rubik by generating a stable knock-in HeLa cell line using CRISPR-Cas9 and single-cell sorting. Our results confirmed the effective functioning of Rubik with Cre and Flp recombinases and showed the ability to induce selective recombination via either tamoxifen or trimethoprim. This system holds potential for neuroscience research, particularly in generating knock-in mice expressing Rubik, which could be instrumental in precisely defining the roles of specific neuronal populations based on Cre and Flp activity.

molecular biology↗

bioRxiv2024

Monitoring myelin lipid composition and structure of myelinated fibers reveals a maturation delay in CMT1A

1.Findings accumulated over time show that neurophysiological, neuropathological, and molecular alterations are present in CMT1A and support the dysmyelinating rather than demyelinating nature of this neuropathy. Moreover, uniform slowing of nerve conduction velocity is already manifest in CMT1A children and does not improve throughout their life. This evidence and our previous studies displaying aberrant myelin composition and structure in adult CMT1A rats prompt us to hypothesize a myelin and axon developmental defect in the CMT1A peripheral nervous system. Peripheral myelination begins during the early stages of development in mammals and, during this process, chemical and structural features of myelinated fibers (MFs) evolve towards a mature phenotype; deficiencies within this self-modulating circuit can cause its blockage. Therefore, to shed light on pathophysiological mechanisms that occur during development, and to investigate the relationship among axonal, myelin, and lipidome deficiencies in CMT1A, we extensively analyzed the evolution of both myelin lipid profile and MF structure in WT and CMT1A rats. Lipidomic analysis revealed a delayed maturation of CMT1A myelin already detectable at P10 characterized by deprivation of sphingolipid species such as hexosylceramides and long-chain sphingomyelins, whose concentration physiologically increases in WT, and an increase in lipids typical of unspecialized plasma membranes, including phosphatidylcholines and phosphatidylethanolamines. Consistently, advanced morphometric analysis on more than 130.000 MFs revealed a delay in the evolution of CMT1A axon and myelin geometric parameters, appearing concomitantly with lipid impairment. We here demonstrate that, during normal development, MFs undergo a continuous maturation process in both chemical composition and physical structure, but these processes are delayed in CMT1A.

neuroscience↗

bioRxiv2019

Genetic inhibition of PCSK9, atherogenic lipoprotein concentrations, and calcific aortic valve stenosis

BackgroundProprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition reduces plasma concentrations of low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apoB) and lipoprotein(a) [Lp(a)]. Atherogenic lipoprotein levels have been linked with calcific aortic valve stenosis (CAVS). Our objectives were to determine the association between variants in PCSK9 and lipoprotein-lipid levels, coronary artery disease (CAD) and CAVS, and to evaluate if PCSK9 could be implicated in aortic valve interstitial cells (VICs) calcification. MethodsWe built a genetic risk score weight for LDL-C levels (wGRS) using 10 independent PCSK9 single nucleotide polymorphisms and determined its association with lipoprotein-lipid levels in 9692 participants of the EPIC-Norfolk study. We investigated the association between the wGRS and CAD and CAVS in the UK Biobank, as well as the association between the PCSK9 R46L variant and CAVS in a meta-analysis of published prospective, population-based studies (Copenhagen studies, 1463 cases/101,620 controls) and unpublished studies (UK Biobank, 1350 cases/349,043 controls, Malmo Diet and Cancer study, 682 cases/5963 controls and EPIC-Norfolk study, 508 cases/20,421 controls). We evaluated PCSK9 expression and localization in explanted aortic valves by capillary Western blot and immunohistochemistry in patients with and without CAVS. Von Kossa staining was used to visualize aortic leaflet calcium deposits. PCSK9 expression under oxidative stress conditions in VICs was assessed. ResultsThe wGRS was significantly associated with lower LDL-C and apoB (p<0.001), but not with Lp(a). In the UK Biobank, the association of PCSK9 variants with CAD were positively correlated with their effects on apoB levels. CAVS was less prevalent in carriers of the PCSK9 R46L variant [odds ratio=0.71 (95% confidence interval, 0.57-0.88), p<0.001]. PCSK9 expression was elevated in the aortic valves of patients with aortic sclerosis and CAVS compared to controls. In calcified leaflets, PCSK9 co-localized with calcium deposits. PCSK9 expression was induced by oxidative stress in VICs. ConclusionGenetic inhibition of PCSK9 is associated with lifelong reductions in the levels of non-Lp(a) apoB-containing lipoproteins as well as lower odds of CAD and CAVS. PCSK9 is abundant in fibrotic and calcified aortic leaflets. Oxidative stress increases PCSK9 expression in VICs. These results provide a rationale for performing randomized clinical trials of PCSK9 inhibition in CAVS.

genetics↗