The Alzheimer susceptibility gene BIN1 induces isoform-dependent neurotoxicity through early endosome defects.

The Bridging Integrator 1 (BIN1) gene is a major susceptibility gene for Alzheimer's disease (AD). Deciphering its pathophysiological role is challenging due to its numerous isoforms. Here we observed in Drosophila that human BIN1 isoform1 (BIN1iso1) overexpression, contrary to human BIN1 isoform8 (BIN1iso8) and human BIN1 isoform9 (BIN1iso9), induced an accumulation of endosomal vesicles and neurodegeneration.

Is autosomal dominant polycystic kidney disease an early sweet disease?

The clinical course of autosomal dominant polycystic kidney disease (ADPKD) starts in childhood. Evidence of the beneficial impact of early nephron-protective strategies and lifestyle modifications on ADPKD prognosis is accumulating. Recent studies have described the association of overweight and obesity with rapid disease progression in adults with ADPKD.

TRP channel expression correlates with the epithelial-mesenchymal transition and high-risk endometrial carcinoma.

Transient receptor potential (TRP) channels excel in cellular sensing as they allow rapid ion influx across the plasma membrane in response to a variety of extracellular cues. Recently, a distinct TRP mRNA expression signature was observed in stromal cells (ESC) and epithelial cells (EEC) of the endometrium, a tissue in which cell phenotypic plasticity is essential for normal functioning. However, it is unknown whether TRP channel mRNA expression is subject to the phenotypic switching that occurs during epithelial to mesenchymal transition (EMT) and mesenchymal to epithelial transition (MET), and whether TRP channel mRNA expression is associated with aggressive phenotypes in endometrial cancer (EC).

A guide to studying protein aggregation.

Disrupted protein folding or decreased protein stability can lead to the accumulation of (partially) un- or misfolded proteins, which ultimately cause the formation of protein aggregates. Much of the interest in protein aggregation is associated with its involvement in a wide range of human diseases and the challenges it poses for large-scale biopharmaceutical manufacturing and formulation of therapeutic proteins and peptides. On the other hand, protein aggregates can also be functional, as observed in nature, which triggered its use in the development of biomaterials or therapeutics as well as for the improvement of food characteristics.

Intratumoral DNA-based delivery of checkpoint-inhibiting antibodies and interleukin 12 triggers T cell infiltration and anti-tumor response.

To improve the anti-tumor efficacy of immune checkpoint inhibitors, numerous combination therapies are under clinical evaluation, including with IL-12 gene therapy. The current study evaluated the simultaneous delivery of the cytokine and checkpoint-inhibiting antibodies by intratumoral DNA electroporation in mice. In the MC38 tumor model, combined administration of plasmids encoding IL-12 and an anti-PD-1 antibody induced significant anti-tumor responses, yet similar to the monotherapies.

Bcl-xL acts as an inhibitor of IPR channels, thereby antagonizing Ca-driven apoptosis.

Anti-apoptotic Bcl-2-family members not only act at mitochondria but also at the endoplasmic reticulum, where they impact Ca dynamics by controlling IP receptor (IPR) function. Current models propose distinct roles for Bcl-2 vs. Bcl-xL, with Bcl-2 inhibiting IPRs and preventing pro-apoptotic Ca release and Bcl-xL sensitizing IPRs to low [IP] and promoting pro-survival Ca oscillations.

Synaptogenic activity of the axon guidance molecule Robo2 underlies hippocampal circuit function.

Synaptic connectivity within adult circuits exhibits a remarkable degree of cellular and subcellular specificity. We report that the axon guidance receptor Robo2 plays a role in establishing synaptic specificity in hippocampal CA1. In vivo, Robo2 is present and required postsynaptically in CA1 pyramidal neurons (PNs) for the formation of excitatory (E) but not inhibitory (I) synapses, specifically in proximal but not distal dendritic compartments.

Highly efficient intercellular spreading of protein misfolding mediated by viral ligand-receptor interactions.

Protein aggregates associated with neurodegenerative diseases have the ability to transmit to unaffected cells, thereby templating their own aberrant conformation onto soluble homotypic proteins. Proteopathic seeds can be released into the extracellular space, secreted in association with extracellular vesicles (EV) or exchanged by direct cell-to-cell contact. The extent to which each of these pathways contribute to the prion-like spreading of protein misfolding is unclear.

Synthetic Pept-Ins as a Generic Amyloid-Like Aggregation-Based Platform for PET Imaging of Intracellular Targets.

Amyloid-like aggregation of proteins is induced by short amyloidogenic sequence segments within a specific protein sequence resulting in self-assembly into β-sheets. We recently validated a technology platform in which synthetic amyloid peptides ("Pept-ins") containing a specific aggregation-prone region (APR) are used to induce specific functional knockdown of the target protein from which the APR was derived, including bacterial, viral, and mammalian cell proteins. In this work, we investigated if Pept-ins can be used as vector probes for Positron Emission Tomography (PET) imaging of intracellular targets.

A workflow for streamlined acquisition and correlation of serial regions of interest in array tomography.

Background: Array tomography (AT) is a high-resolution imaging method to resolve fine details at the organelle level and has the advantage that it can provide 3D volumes to show the tissue context. AT can be carried out in a correlative way, combing light and electron microscopy (LM, EM) techniques. However, the correlation between modalities can be a challenge and delineating specific regions of interest in consecutive sections can be time-consuming.

TRPM4 links calcium signaling to membrane potential in pancreatic acinar cells.

Transient receptor potential cation channel subfamily M member 4 (TRPM4) is a Ca-activated nonselective cation channel that mediates membrane depolarization. Although, a current with the hallmarks of a TRPM4-mediated current has been previously reported in pancreatic acinar cells (PACs), the role of TRPM4 in the regulation of acinar cell function has not yet been explored. In the present study, we identify this TRPM4 current and describe its role in context of Ca signaling of PACs using pharmacological tools and TRPM4-deficient mice.

Unstable regulatory T cells, enriched for naïve and Nrp1 cells, are purged after fate challenge.

Regulatory T cells (T) are indispensable for the control of immune homeostasis and have clinical potential as a cell therapy for treating autoimmunity. T can lose expression of the lineage-defining Foxp3 transcription factor and acquire effector T cell (T) characteristics, a process referred to as T plasticity. The extent and reversibility of such plasticity during immune responses remain unknown.

A prion-like protein regulator of seed germination undergoes hydration-dependent phase separation.

Many organisms evolved strategies to survive desiccation. Plant seeds protect dehydrated embryos from various stressors and can lay dormant for millennia. Hydration is the key trigger to initiate germination, but the mechanism by which seeds sense water remains unresolved.

Bacterial Protein Homeostasis Disruption as a Therapeutic Intervention.

Cells have evolved a complex molecular network, collectively called the protein homeostasis (proteostasis) network, to produce and maintain proteins in the appropriate conformation, concentration and subcellular localization. Loss of proteostasis leads to a reduction in cell viability, which occurs to some degree during healthy ageing, but is also the root cause of a group of diverse human pathologies. The accumulation of proteins in aberrant conformations and their aggregation into specific beta-rich assemblies are particularly detrimental to cell viability and challenging to the protein homeostasis network.

Induced pluripotent stem cell-derived motor neurons of CMT type 2 patients reveal progressive mitochondrial dysfunction.

Axonal Charcot-Marie-Tooth neuropathies (CMT type 2) are caused by inherited mutations in various genes functioning in different pathways. The types of genes and multiplicity of mutations reflect the clinical and genetic heterogeneity in CMT2 disease, which complicates its diagnosis and has inhibited the development of therapies. Here, we used CMT2 patient-derived pluripotent stem cells (iPSCs) to identify common hallmarks of axonal degeneration shared by different CMT2 subtypes.

Mapping the expression of transient receptor potential channels across murine placental development.

Transient receptor potential (TRP) channels play prominent roles in ion homeostasis by their ability to control cation influx. Mouse placentation is governed by the processes of trophoblast proliferation, invasion, differentiation, and fusion, all of which require calcium signaling. Although certain TRP channels have been shown to contribute to maternal-fetal transport of magnesium and calcium, a role for TRP channels in specific trophoblast functions has been disregarded.

The Nanoscopic Organization of Synapse Structures: A Common Basis for Cell Communication.

Synapse structures, including neuronal and immunological synapses, can be seen as the plasma membrane contact sites between two individual cells where information is transmitted from one cell to the other. The distance between the two plasma membranes is only a few tens of nanometers, but these areas are densely populated with functionally different proteins, including adhesion proteins, receptors, and transporters. The narrow space between the two plasma membranes has been a barrier for resolving the synaptic architecture due to the diffraction limit in conventional microscopy (~250 nm).

The role of Bcl-2 proteins in modulating neuronal Ca signaling in health and in Alzheimer's disease.

The family of B-cell lymphoma-2 (Bcl-2) proteins exerts key functions in cellular health. Bcl-2 primarily acts in mitochondria where it controls the initiation of apoptosis. However, during the last decades, it has become clear that this family of proteins is also involved in controlling intracellular Ca signaling, a critical process for the function of most cell types, including neurons.

Alzheimer's disease.

In this Seminar, we highlight the main developments in the field of Alzheimer's disease. The most recent data indicate that, by 2050, the prevalence of dementia will double in Europe and triple worldwide, and that estimate is 3 times higher when based on a biological (rather than clinical) definition of Alzheimer's disease. The earliest phase of Alzheimer's disease (cellular phase) happens in parallel with accumulating amyloid β, inducing the spread of tau pathology.

MAPRE2 mutations result in altered human cranial neural crest migration, underlying craniofacial malformations in CSC-KT syndrome.

Circumferential skin creases (CSC-KT) is a rare polymalformative syndrome characterised by intellectual disability associated with skin creases on the limbs, and very characteristic craniofacial malformations. Previously, heterozygous and homozygous mutations in MAPRE2 were found to be causal for this disease. MAPRE2 encodes for a member of evolutionary conserved microtubule plus end tracking proteins, the end binding (EB) family.