Biology subjects

Herz, J.

Publications and source records attributed to Herz, J..

8 recordsLinked to original sources

bioRxiv2026

An Apoptotic Failsafe Program Involving PDGF-dependent PI 3-Kinase Activity Contributes to Plaque Composition in Atherosclerosis

Background: Growth and stability of atherosclerotic plaques are impacted by vascular smooth muscle cell (VSMC) apoptosis which is believed to be suppressed by growth factor dependent activation of phosphoinositide 3-kinase (PI3K). Here, we analyzed the effects of chronically elevated platelet-derived growth factor receptor {beta} (PDGFR{beta}) signaling on VSMC apoptosis and aortic plaque composition during atherogenesis. Methods: We assessed atherosclerosis in low-density lipoprotein receptor deficient mice, lacking low-density lipoprotein receptor-related protein 1 in VSMCs (LDLR-/-smLRP1-/- mice), in that smLRP1 deficiency resulted in PDGFRB overexpression. Apoptosis and downstream signaling was investigated in cultured aortic VSMCs. Results: Chronically elevated PDGFR{beta} signaling in LDLR-/-smLRP1-/- mice unexpectedly increased VSMC apoptosis in atherosclerotic plaques. In vitro, PDGF exerted transient anti-apoptotic effects on VSMCs, whereas long-term stimulation promoted cell death. Mutation of the PI3K binding site in the PDGFR{beta} (PDGFR{beta}-F2/F2) reduced VSMC apoptosis in plaques as well as in cultured VSMCs. Further analyses revealed that PI3K isoform p110 mediates VSMC survival, whereas p110{delta} and p110{beta} rather promote apoptosis. We identified a pro-apoptotic PDGFR{beta}-driven signaling pathway in VSMCs involving PI3K-dependent induction of c-Myc that in turn suppresses the expression of anti-apoptotic Bcl-2. PDGF-dependent downregulation of Bcl-2 increases the susceptibility of VSMCs to apoptotic agonists like H2O2 or Fas ligand. Consistently, Bcl-2 expression was elevated in plaques from PDGFR{beta}-F2/F2 mice. Conclusions: Our study expands the understanding of the role of growth factors in regulating apoptosis and argues against their role as pure survival factors. This has direct implications in atherogenesis, as chronically elevated PDGF does not mediate VSMC survival in atherosclerotic plaques, but rather promotes cell death in the VSMC-rich fibrous cap, thus promoting plaque instability and rupture.

biochemistry↗

bioRxiv2026

Distinct core minor pilin complexes prime specialized type IV filaments in cyanobacteria

The model cyanobacterium, Synechocystis sp. PCC 6803 encodes in addition to the major pilin of the Type IV pilus filament, an extensive, partially uncharacterized repertoire of minor pilins. For those cyanobacterial minor pilins that have been characterized, their roles span a surprisingly diverse range of functions. To elucidate the roles of uncharacterized minor pilins in a systematic way, we applied structural phylogenomics across 90 genomes, classifying cyanobacterial pilins into six conserved families that form two distinct putative core priming complexes. We demonstrate that these complexes initiate the assembly of two morphologically distinct Type IV pilus filaments: short, hyper-dynamic pili for natural competence, and long, adhesive pili for motility and phototaxis. Structural analysis revealed a conserved beta-solenoid domain in PilX subunits, which we propose fulfills the "tip plug" function of PilY1 homologs. Proteomic data indicate that the minor pilin PilX2 facilitates the assembly of motility pili, which is required to maintain DnaJ3 co-chaperone levels and trigger cAMP-dependent surface sensing. These findings challenge the concept of a single multipurpose pilus, establishing that cyanobacteria operate two specialized nanomachines optimized for the conflicting biophysical requirements of DNA uptake and surface motility.

microbiology↗

bioRxiv2025

DISTINCT LYSOSOMAL DYSFUNCTION PATTERNS OF PROGRANULIN DEFICIENCY IN THE CNS IMPLICATE PROGRANULIN IN CELL TYPE-SPECIFIC PROTEIN SORTING

Loss-of-function mutations in Progranulin (GRN) cause neuronal ceroid lipofuscinosis (NCL) and hereditary frontotemporal dementia, presumably through lysosomal dysfunction. Lysosomes are key metabolic organelles whose functions vary widely depending on their cell type of origin. These functional variations are driven by the lysosomal proteome, yet whether progranulin deficiency alters the lysosomal composition of the mammalian brain in a cell type-specific manner has not been tested. To answer this unknown, we used cell type-specific LysoIP to perform tandem-mass-tag mass-spectrometry and detected distinct aberrant proteomic signatures in progranulin-deficient astrocytes, neurons, and microglia, indicating cell type-specific dysregulation of key lysosomal proteins with crucial functions in sphingolipid metabolism and lysosome organization. These proteins markedly differed from progranulin-deficient RNAseq data sets, suggesting progranulin regulates lysosomal composition through post-translational mechanisms including the sorting of nascent proteins to the lysosome. Validation experiments confirmed that Mfsd8 and Ppt1, proteins whose mutations on their own cause NCL, were essentially absent from progranulin-deficient neuronal and microglial lysosomes, respectively. Our findings demonstrate the protein composition of lysosomes are uniquely sensitive to progranulin deficiency in a cell type-specific manner and that progranulin may function as an essential hub for endolysosomal homeostasis.

neuroscience↗

bioRxiv2025

CD33 and Clusterin Interact Biophysically and Genetically to Modulate Alzheimer Risk

We report the results of structural, functional and genetic studies on the CD33 sialic acid- binding receptor that reveal how non-coding variants in CD33 alter risk for Alzheimers disease (AD). The full-length CD33M isoform, whose expression is upregulated by non-coding AD-risk alleles, preferentially forms dimers at the cell surface, where they interact with AD-related proteins (clusterin and A{beta}). This interaction induces CD33M inhibitory signalling and downregulates protective microglial functions including phagocytic removal of amyloid plaques. Human brain expression quantitative trait loci (eQTL) and causal mediation analyses confirm that quantitative interactions between CLU and CD33 genotypes modulate AD phenotypes and suggest that genotypes at these loci might be used to personalise future therapeutic approaches. Our work also highlights several other unexpected aspects of CD33 biology, including a soluble shed extracellular fragment of CD33M and a similar soluble secreted product arising from a truncating mutation in the CD33 extracellular domain (CD33M{Delta}4bp).

neuroscience↗

bioRxiv2025

Ms4a4a deficiency ameliorates plaque pathology in a mouse model of amyloid accumulation

Genome-wide association studies for Alzheimer disease (AD) risk have identified a number of genes enriched in microglia, including MS4A4A. Common variants in MS4A4A influence AD risk, MS4A4A expression, TREM2 signaling, and a specific microglial transcriptional state, though the exact role of MS4A4A in AD remains unclear. Using a mouse model of amyloid beta (A{beta}) accumulation (5xFAD), we examined the impact of Ms4a4a loss on A{beta} pathology. Before A{beta} accumulation, Ms4a4a loss reduces steady-state A{beta} levels and shortens A{beta} half-life in brain interstitial fluid. In aged 5xFAD Ms4a4a-deficient mice, plaques are more compact with reduced overall plaque burden. Microglia lacking Ms4a4a are more pro-inflammatory and produce more MMP-9, which may promote degradation of A{beta} and A{beta} fibrils. Human subjects that carry a variant near MS4A4A (rs1582763) that confers resilience to AD also exhibit significantly elevated levels of MMP-9 in their cerebrospinal fluid. Together, our results suggest that loss of Ms4a4a improves A{beta} pathology by altering A{beta} clearance, offering insights for therapeutic interventions in AD.

neuroscience↗

bioRxiv2021

Endosomal Acidification by NHE6-depletion Corrects ApoE4-mediated Synaptic Impairments and Reduces Amyloid Plaque Load

Apolipoprotein E4 (ApoE4) is the most important and prevalent risk factor for late-onset Alzheimers disease (AD). The isoelectric point of ApoE4 matches the pH of the early endosome (EE), causing its delayed dissociation from ApoE receptors and hence impaired endolysosomal trafficking, disruption of synaptic homeostasis and reduced amyloid clearance. We have shown that enhancing endosomal acidification by inhibiting the EE-specific sodium-hydrogen exchanger NHE6 restores vesicular trafficking and normalizes synaptic homeostasis. Remarkably and unexpectedly, loss of NHE6 effectively suppressed amyloid deposition even in the absence of ApoE4, suggesting that accelerated acidification of early endosomes caused by the absence of NHE6 occludes the effect of ApoE on amyloid plaque formation. NHE6 suppression or inhibition may thus be a universal, ApoE-independent approach to prevent amyloid buildup in the brain. These findings suggest a novel therapeutic approach for the prevention of AD by which partial NHE6 inhibition reverses the ApoE4 induced endolysosomal trafficking defect and reduces amyloid.

neuroscience↗

bioRxiv2021

GABAergic neuronal IL-4R mediates T cell effect on memory

Mechanisms governing how immune cells and their derived molecules impact homeostatic brain function are still poorly understood. Here, we elucidate neuronal mechanisms underlying effects of T cells on synaptic function and episodic memory. Depletion of CD4 T cells led to memory deficits and impaired long term potentiation. Severe combined immune-deficient (SCID) mice exhibited amnesia, which was reversible by repopulation with T cells from wild-type but not from IL-4-knockout mice. This rescue was mediated via IL-4 receptors (IL-4R) expressed on neurons. Exploration of snRNAseq of neurons participating in memory processing provided insights into synaptic organization and plasticity-associated pathways and genes regulated by immune cells and molecules. IL-4R knockout in inhibitory neurons impaired contextual fear memory, suggesting participation of an IL-4-associated switch in regulating synaptic function and promoting contextual fear memory. These findings provide insights into neuroimmune interactions at the transcriptional and functional levels in neurons.

neuroscience↗

bioRxiv2020

CD11c+CD88+CD317+ myeloid cells are critical mediators of persistent CNS autoimmunity

BackgroundNatalizumab, a humanized monoclonal antibody (mAb) against 4-integrin, reduces the number of dendritic cells (DC) in cerebral perivascular spaces in multiple sclerosis (MS). Selective deletion of 4-integrin in CD11c+ cells should curtail their migration to the CNS and ameliorate experimental autoimmune encephalomyelitis (EAE). MethodsWe generated CD11c.Cre+/-ITGA4fl/fl C57/Bl6 mice to selectively delete 4-integrin in CD11c+ cells. Active immunization and adoptive transfer EAE models were employed. Multi-parameter flow cytometry was utilized to immunophenotype leukocytes. Single-cell RNA sequencing (scRNA-seq) was used to profile individual cells. Results4-integrin expression by CD11c+ cells was significantly reduced in primary and secondary lymphoid organs in CD11c.Cre+/-ITGA4fl/fl mice. In active EAE, a delayed disease onset was observed in CD11c.Cre+/-ITGA4fl/fl mice, during which CD11c+CD88+ cells were sequestered in the blood. Upon EAE onset, CD11c+CD88+ cells accumulated in the CNS and expressed CD317+. In adoptive transfer experiments, CD11c.Cre+/-ITGA4fl/fl mice had ameliorated clinical disease associated with diminished numbers of CNS CD11c+CD88+CD317+ cells. The transcription profile of CD11c+CD88+CD317+ cells placed them within previously defined microglia-like cells in human CSF. We show that activated, but not naive microglia expressed CD11c, CD88, and CD317. Finally, anti-CD317 treatment prior to clinical EAE substantially enhanced recovery. ConclusionCD11c+CD88+CD317+ cells in the CNS promote inflammatory damage. Transcriptional analysis identifies CD11c+CD88+CD317+ cells as a unique myeloid subset in human CSF. The disease-propagating effects of these cells can be antagonized using anti-CD317 mAb.

immunology↗