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The cyanobacterial saxitoxin exacerbates neural cell death and brain malformations induced by Zika virus.
The northeast (NE) region of Brazil commonly goes through drought periods, which favor cyanobacterial blooms, capable of producing neurotoxins with implications for human and animal health. The most severe dry spell in the history of Brazil occurred between 2012 and 2016. Coincidently, the highest incidence of microcephaly associated with the Zika virus (ZIKV) outbreak took place in the NE region of Brazil during the same years. In this work, we tested the hypothesis that saxitoxin (STX), a neurotoxin produced in South America by the freshwater cyanobacteria Raphidiopsis raciborskii, could have contributed to the most severe Congenital Zika Syndrome (CZS) profile described worldwide. Quality surveillance showed higher cyanobacteria amounts and STX occurrence in human drinking water supplies of NE compared to other regions of Brazil. Experimentally, we described that STX doubled the quantity of ZIKV-induced neural cell death in progenitor areas of human brain organoids, while the chronic ingestion of water contaminated with STX before and during gestation caused brain abnormalities in offspring of ZIKV-infected immunocompetent C57BL/6J mice. Our data indicate that saxitoxin-producing cyanobacteria is overspread in water reservoirs of the NE and might have acted as a co-insult to ZIKV infection in Brazil. These results raise a public health concern regarding the consequences of arbovirus outbreaks happening in areas with droughts and/or frequent freshwater cyanobacterial blooms.
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Progranulin deficiency in the brain: the interplay between neuronal and non-neuronal cells.
Heterozygous mutations in GRN gene lead to insufficient levels of the progranulin (PGRN) protein, resulting in frontotemporal dementia (FTD) with TAR DNA-binding protein 43 (TDP-43) inclusions, classified pathologically as frontotemporal lobar degeneration (FTLD-TDP). Homozygous GRN mutations are exceedingly rare and cause neuronal ceroid lipofuscinosis 11, a lysosomal storage disease with onset in young adulthood, or an FTD syndrome with late-onset manifestations. In this review, we highlight the broad spectrum of clinical phenotypes associated with PGRN deficiency, including primary progressive aphasia and behavioral variant of frontotemporal dementia. We explore these phenotypes alongside relevant rodent and in vitro human models, ranging from the induced pluripotent stem cell-derived neural progenitors, neurons, microglia, and astrocytes to genetically engineered heterotypic organoids containing both neurons and astrocytes. We summarize advantages and limitations of these models in recapitulating the main FTLD-GRN hallmarks, highlighting the role of non-cell-autonomous mechanisms in the formation of TDP-43 pathology, neuroinflammation, and neurodegeneration. Data obtained from patients' brain tissues and biofluids, in parallel with single-cell transcriptomics, demonstrate the complexity of interactions among the highly heterogeneous cellular clusters present in the brain, including neurons, astrocytes, microglia, oligodendroglia, endothelial cells, and pericytes. Emerging evidence has revealed that PGRN deficiency is associated with cell cluster-specific, often conserved, genetic and molecular phenotypes in the central nervous system. In this review, we focus on how these distinct cellular populations and their dysfunctional crosstalk contribute to neurodegeneration and neuroinflammation in FTD-GRN. Specifically, we characterize the phenotypes of lipid droplet-accumulating microglia and alterations of myelin lipid content resulting from lysosomal dysfunction caused by PGRN deficiency. Additionally, we consider how the deregulation of glia-neuron communication affects the exchange of organelles such as mitochondria, and the removal of excess toxic products such as protein aggregates, in PGRN-related neurodegeneration.
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Editorial: New advances on hypothalamus-pituitary stem cell biology.
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Constitutive activation of canonical Wnt signaling disrupts choroid plexus epithelial fate.
The choroid plexus secretes cerebrospinal fluid and is critical for the development and function of the brain. In the telencephalon, the choroid plexus epithelium arises from the Wnt- expressing cortical hem. Canonical Wnt signaling pathway molecules such as nuclear β-CATENIN are expressed in the mouse and human embryonic choroid plexus epithelium indicating that this pathway is active. Point mutations in human β-CATENIN are known to result in the constitutive activation of canonical Wnt signaling. In a mouse model that recapitulates this perturbation, we report a loss of choroid plexus epithelial identity and an apparent transformation of this tissue to a neuronal identity. Aspects of this phenomenon are recapitulated in human embryonic stem cell derived organoids. The choroid plexus is also disrupted when β-Catenin is conditionally inactivated. Together, our results indicate that canonical Wnt signaling is required in a precise and regulated manner for normal choroid plexus development in the mammalian brain.
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miRNA regulation in brain tissue space: the 3'UTR perspective.
MicroRNAs (miRNAs) are key regulators of gene expression in both health and disease. Their expression and regulatory functions are highly complex and spatiotemporally organized within tissues. In recent years, spatial transcriptomics has made significant progress in quantifying RNA expression at subcellular resolution in tissue sections. However, no current method can quantify miRNAs and their target 3' untranslated regions (3'UTRs) in space simultaneously. Furthermore, although 3'UTRs harbor critical miRNA target sites, 3'UTR isoform variation in space is largely unexplored. In this review, we discuss the role of miRNA-mediated regulation. We focus on neurodevelopment and neuronal function, where miRNAs and 3'UTRs have particularly complex and important functions. We summarize current experimental and computational approaches for spatial quantification of miRNAs and 3'UTRs, highlight existing challenges, and propose strategies for future research.
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Identification of MACF1 as a causative gene of generalised epilepsy.
BACKGROUND: The microtubule actin crosslinking factor 1 (MACF1) gene encodes microtubule-microfilament cross-linking factor 1 that plays an essential role in the embryonic brain development. MACF1 variants were associated with lissencephaly-9 (LIS9). However, the MACF1-epilepsy relationship was unknown. METHODS: Trios-based whole-exome sequencing was performed on a cohort with generalised epilepsy from the China Epilepsy Gene 1.0 project. The spatial-temporal expression, single-cell sequencing and genotype-phenotype correlation were analysed to explore the role of MACF1 in epilepsy and neurodevelopment. RESULTS: Two de novo heterozygous and eight biallelic MACF1 variants were identified in 10 unrelated patients. The variants presented significantly high excess by multiple statistical analyses. All patients were diagnosed with generalised epilepsy, among whom three patients presented with neurodevelopmental delay. MACF1 was expressed throughout the lifespan, with three major peaks in the fetal, early childhood and adulthood stages, consistent with seizure onset ages of the patients. The highest expression in adulthood was in the thalamus nucleus, potentially associated with the pathogenesis of generalised epilepsy. The single-cell sequencing in organoids showed MACF1 is widely expressed in the developing brain, especially in the early stage, suggesting a vital role in neurodevelopment. Genotype-phenotype association analysis revealed that LIS9-associated variants were featured by de novo monoallelic variants clustered within the C-terminal; the autism spectrum disorder-associated variants were mainly de novo monoallelic variants located at the spectrin-repeat rod domains. In contrast, the epilepsy-associated variants were biallelic missense variants, and those in the plakin domain were potentially associated with neurodevelopment delay. SIGNIFICANCE: MACF1 is potentially a novel causative gene of generalised epilepsy.
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Anti-herpetic tau preserves neurons via the cGAS-STING-TBK1 pathway in Alzheimer's disease.
Alzheimer's disease (AD) diagnosis relies on the presence of extracellular β-amyloid (Aβ) and intracellular hyperphosphorylated tau (p-tau). Emerging evidence suggests a potential link between AD pathologies and infectious agents, with herpes simplex virus 1 (HSV-1) being a leading candidate. Our investigation, using metagenomics, mass spectrometry, western blotting, and decrowding expansion pathology, detects HSV-1-associated proteins in human brain samples. Expression of the herpesvirus protein ICP27 increases with AD severity and strongly colocalizes with p-tau but not with Aβ. Modeling in human brain organoids shows that HSV-1 infection elevates tau phosphorylation. Notably, p-tau reduces ICP27 expression and markedly decreases post-infection neuronal death from 64% to 7%. This modeling prompts investigation into the cGAS-STING-TBK1 pathway products, nuclear factor (NF)-κB and IRF-3, which colocalizes with ICP27 and p-tau in AD. Furthermore, experimental activation of STING enhances tau phosphorylation, while TBK1 inhibition prevents it. Together, these findings suggest that tau phosphorylation acts as an innate immune response in AD, driven by cGAS-STING.
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AI-Validated Brain Targeted mRNA Lipid Nanoparticles with Neuronal Tropism.
Targeting therapeutic nanoparticles to the brain poses a challenge due to the restrictive nature of the blood-brain barrier (BBB). Here we report the development of mRNA-loaded lipid nanoparticles (LNPs) functionalized with BBB-interacting small molecules, thereby enhancing brain delivery and gene expression. Screening brain-targeted mRNA-LNPs in central nervous system (CNS) in vitro models and through intravenous administration in mice demonstrated that acetylcholine-conjugated LNPs achieved superior brain tropism and gene expression, outperforming LNP modifications with nicotine, glucose, memantine, cocaine, tryptophan, and other small molecules. An artificial intelligence (AI)-based model designed to predict the BBB permeability of small-molecule ligands showed strong alignment with our experimental results, providing in vivo validation of its predictive capacity. Cell-specific biodistribution analysis in Cre-reporter Ai9 mice showed that acetylcholine-functionalized LNPs preferentially transfected neurons and astrocytes following either intravenous or intracerebral administration. Mechanistic studies suggest that acetylcholine-LNP uptake is mediated by the functional engagement of acetylcholine receptors (AchRs) followed by endocytosis, which synergistically enhances intracellular mRNA delivery. Moreover, acetylcholine-LNPs successfully crossed a human BBB-on-a-chip model, enabling transgene expression in human iPSC-derived neurons. Their effective penetration and transfection in human brain organoids further support their potential activity in human-based systems. These findings establish a predictive and modular framework for engineering CNS-targeted LNPs, advancing precision gene delivery for brain disorders.
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Engineering Toxoplasma gondii secretion systems for intracellular delivery of multiple large therapeutic proteins to neurons.
Delivering macromolecules across biological barriers such as the blood-brain barrier limits their application in vivo. Previous work has demonstrated that Toxoplasma gondii, a parasite that naturally travels from the human gut to the central nervous system (CNS), can deliver proteins to host cells. Here we engineered T. gondii's endogenous secretion systems, the rhoptries and dense granules, to deliver multiple large (>100 kDa) therapeutic proteins into neurons via translational fusions to toxofilin and GRA16. We demonstrate delivery in cultured cells, brain organoids and in vivo, and probe protein activity using imaging, pull-down assays, scRNA-seq and fluorescent reporters. We demonstrate robust delivery after intraperitoneal administration in mice and characterize 3D distribution throughout the brain. As proof of concept, we demonstrate GRA16-mediated brain delivery of the MeCP2 protein, a putative therapeutic target for Rett syndrome. By characterizing the potential and current limitations of the system, we aim to guide future improvements that will be required for broader application.
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Mitochondrial HSF1 triggers mitochondrial dysfunction and neurodegeneration in Huntington's disease.
Aberrant localization of proteins to mitochondria disturbs mitochondrial function and contributes to the pathogenesis of Huntington's disease (HD). However, the crucial factors and the molecular mechanisms remain elusive. Here, we found that heat shock transcription factor 1 (HSF1) accumulates in the mitochondria of HD cell models, a YAC128 mouse model, and human striatal organoids derived from HD induced pluripotent stem cells (iPSCs). Overexpression of mitochondria-targeting HSF1 (mtHSF1) in the striatum causes neurodegeneration and HD-like behavior in mice. Mechanistically, mtHSF1 facilitates mitochondrial fission by activating dynamin-related protein 1 (Drp1) phosphorylation at S616. Moreover, mtHSF1 suppresses single-stranded DNA-binding protein 1 (SSBP1) oligomer formation, which results in mitochondrial DNA (mtDNA) deletion. The suppression of HSF1 mitochondrial localization by DH1, a unique peptide inhibitor, abolishes HSF1-induced mitochondrial abnormalities and ameliorates deficits in an HD animal model and human striatal organoids. Altogether, our findings describe an unsuspected role of HSF1 in contributing to mitochondrial dysfunction, which may provide a promising therapeutic target for HD.