Biology subjects

Aguzzi, A.

Publications and source records attributed to Aguzzi, A..

At least 19 recordsLinked to original sources

bioRxiv2026

PODXL regulates the neuronal entry of α-synuclein aggregates

Cell-to-cell transmission of -synuclein (-Syn) aggregates is a key event in Parkinson's disease (PD) pathogenesis, yet the neuronal surface factors that govern uptake of pathogenic -Syn fibrils remain undefined. We developed a flow cytometry-based CRISPR activation screen for modifiers of -Syn preformed fibril (PFF) uptake by human iPSC-derived cortical neurons. By interrogating 68 genes encoding cell-surface proteins prioritised by PD genetic associations, we identified podocalyxin-like protein 1 (PODXL) as a strong suppressor of -Syn fibril uptake. High-content imaging and PODXL cDNA overexpression confirmed reduced PFF uptake. Stable PODXL overexpression also reduced PFF-seeded pSynSer129 accumulation and uptake of structurally distinct recombinant and disease-derived -Syn fibrils. Conversely, shRNA-mediated PODXL knockdown increased -Syn PFF uptake, and analysis of PODXL domain-deletion and N-glycosylation mutants suggested that the ectodomain and N-glycosylation contribute to the PODXL-mediated reduction in uptake. Transcriptomic profiling further identified membrane metalloendopeptidase (MME) as a PODXL-responsive candidate mediator. MME activation and treatment with conditioned medium from MME-activated neurons reduced PFF uptake. Thiorphan, an MME inhibitor, partially attenuated the PODXL-associated reduction in uptake. Together, our findings identify PODXL as a neuronal brake on -Syn uptake and implicate its glycan-dependent surface properties together with MME-associated extracellular activity.

neuroscience↗

bioRxiv2026

A CRISPR-Cas9 platform for primary human hepatocytes enables arrayed screening and in vivo validation of HBV host factors

More than two million deaths annually are attributed to liver-related conditions, making primary human hepatocytes (PHH) an invaluable in vitro model for studying liver pathophysiology and the molecular mechanisms underlying hepatic diseases. However, because PHH do not proliferate in culture, CRISPR gene editing has been highly inefficient. Here, we report lipofection- and lentivirus-mediated protocols for CRISPR-Cas9 delivery in mouse-passaged primary human hepatocytes (mpPHH), a system that enables PHH expansion in liver-humanized mice. We achieve robust gene editing efficiencies exceeding 90% in mpPHH while maintaining cell viability. We demonstrate the utility of these protocols by disrupting CYP3A4 to impair xenobiotic metabolism and by showing that edited mpPHH efficiently engraft and expand in mice, generating liver-humanized animals. We establish the feasibility of arrayed CRISPR screening in mpPHH using an 85-gene screen to identify host factors influencing hepatitis B virus (HBV) infection, and validate key findings in humanized mice by targeting the HBV entry receptor SLC10A1 (NTCP), which reduced viral infection in vivo. Our methodology enables scalable genetic manipulation of mpPHH, opening new avenues for HBV research and liver disease modeling.

genomics↗

bioRxiv2026

Adgrd1 deficiency reveals increased hippocampal vulnerability and selective behavioral alterations in mice

ADGRD1 (GPR133) is an orphan adhesion G protein-coupled receptor (aGPCR) that primarily signals through Gs to regulate intracellular cAMP levels and is increasingly recognized for its roles across multiple tissues, including the central nervous system. Its conserved expression in neural tissues, the presence of splice variants in the fetal brain, and its structural similarity to other aGPCRs all suggest that it might play important roles in the organization of neural circuits. Recent studies have identified a wide range of extracellular, membrane- associated, and intracellular interacting partners, highlighting the receptors ability to integrate diverse signals. In this study, we explored the consequences of Adgrd1 deficiency in mice using behavioral, electrophysiological, and transcriptomic approaches. Adgrd1-null mice showed reduced nest-building behavior and decreased exploratory drive, while motor coordination and recognition memory remained largely intact. Electrophysiological recordings indicated a trend toward impaired long-term potentiation. These mice also exhibit increased susceptibility to kainate-induced excitotoxicity. RNA-seq analysis revealed coordinated changes in genes associated with inhibitory signaling, extracellular matrix organization, and cytoskeletal regulation, pointing to a shift toward reduced synaptic stabilization and increased hippocampal vulnerability. Altogether, these results suggest that Adgrd1 plays a key role in maintaining hippocampal resilience and regulating motivational behaviors through integrated molecular and circuit-level mechanisms.

neuroscience↗

bioRxiv2026

Computationally engineered cyclic peptides reduce prion levels in vitro

Prion diseases are neurodegenerative disorders associated with the structural conversion of the cellular prion protein (PrPc) into its misfolded infectious isoform (PrPSc). Despite substantial efforts, no disease-modifying therapy or cure is currently available. Here, we present an integrated computational-experimental pipeline for the rational design of cyclic peptides targeting PrPc to inhibit its pathogenic conversion. Starting from crystal structures of antibody-bound mouse PrPc, we develop a rational design strategy combined with iterative molecular dynamics simulations and sequence optimization to generate peptides with enhanced binding and structural impact. Three candidates were selected for experimental validation. Our results show that [Formula] (49YGPDPSDSYT58, antibody numbering) that binds stably to the 2-3 interface most effectively reduced PrPSc levels in GT1-7 cells, essentially by inducing allosteric re-arrangements that reinforce the intramolecular helical bundle. [Formula] (89GQSNTKPYT97) and [Formula] (89RQSNTWPYT97) binding the {beta}1-1/3 junction exerted more modest effects due to the potential competition of the flexible tail to bind at this site. These results establish a mechanistic link between peptide-induced stabilization of PrPc and inhibition of prion propagation and provide a generalizable framework for designing conformational stabilizers of aggregation-prone proteins.

biophysics↗

bioRxiv2026

Genome-wide arrayed CRISPR activation screen for prion protein modulators

The cellular prion protein (PrPC) is an essential substrate for prion propagation, and its abundance strongly influences susceptibility to prion disease. To systematically identify genetic regulators of PrPC abundance, we performed an arrayed genome-wide CRISPR activation (CRISPRa) screen targeting 19,839 human protein-coding genes in human glioblastoma cells. Using a quantitative time-resolved fluorescence resonance energy transfer (TR-FRET) immunoassay, we measured PrPC levels across 22,442 individual genetic perturbations. This screen identified 531 genes whose activation significantly modulated PrPC abundance. A curated subset of 50 candidates was subjected to validation using independent TR-FRET assays and Western blotting, confirming 45 (90%) of tested hits. All raw and processed screening data, metadata, and analysis code are publicly available. This dataset provides a comprehensive resource for studying genetic regulation of PrPC homeostasis and enables reuse for investigations of membrane protein trafficking, proteostasis, and prion biology.

neuroscience↗

bioRxiv2026

Altered Crosstalk of Bacterial Lipopolysaccharide with Immune Cells in Colorectal Cancer Compared to Paired Adjacent Intestinal Tissue

Commensal bacteria play a crucial role in modulating human immune responses in the intestine. Under homeostatic conditions, gut microbiota are tightly regulated by interactions with the mucosal immune system. However, colorectal cancer (CRC) is characterized by an imbalance in bacterial composition and bacterial translocation across the intestinal barrier. The spatial distribution of bacteria and their interactions with immune cells in CRC tumors are poorly understood. By applying 3D light-sheet imaging, spatial transcriptomics, and imaging mass cytometry to patient-derived CRC and adjacent tissue, bacterial lipopolysaccharide (LPS) is visualized alongside immune cells and vessels. The results show regional bacterial LPS accumulation and colocalization with distinct immune cell subsets. In CRC-adjacent tissue, bacterial LPS is mainly associated with CD11c+ dendritic cells, CD15+ neutrophils, and CD163+ macrophages. In matched CRC tissue, the number and LPS colocalization of CD163+ macrophages and CD11c+ dendritic cells decreased, while CD15+ neutrophils and their colocalization with LPS increased. Notably, immune cell composition and immune cell-bacteria interactions differ between tumor and adjacent tissue, offering insights into host-microbiota dynamics and mechanistic interactions.

cancer biology↗

bioRxiv2025

Lysosomal escape and TMEM106B fibrillar core determine TDP-43 seeding outcomes

Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) shows striking clinical and neuropathological heterogeneity, yet a systematic analysis of subtype-specific features and inter-patient variability was missing. We treated human neurons and neuron-like cells with 30 postmortem brain samples and quantified neoaggregate formation, loss of function and changes in the TDP-43 interactome to define determinants of seeding outcomes. Potent FTLD-TDP-A seeds drove a progressive collapse of physiological TDP-43 interactions accompanied by functional loss. Beyond the burden of pathological TDP-43, we identified the fibrillar core of the lysosomal protein TMEM106B as a critical pro-seeding factor. Transient lysosomal injury markedly enhanced neoaggregation and loss of function, likely by promoting fibril interactions with native TDP-43. Our work establishes a mechanistic link between TMEM106B and TDP-43 aggregation, identifies lysosomal escape as a key driver of pathology and introduces the strongest model yet for seeded TDP-43 aggregation and loss of function, to enable discovery of disease modifiers.

neuroscience↗

bioRxiv2025

The Bone Morphogenetic Pathway Controls the Uptake of Infectious Prions

Prions propagate through cycles of intracellular replication, release, and uptake by host cells. Each of these steps is required for disease progression. Here, we used dCAS9-VP64 mediated transactivation to screen for determinants of prion uptake. We transduced PRNP-/- SH-SY5Y cells with a post-pooled human quadruple-guide-RNA library targeting all transcription start sites of the protein-coding genome, exposed them to synthetic infectious prions, and identified modifiers of prion internalization. Specificity was tested by counterscreens with other neurodegeneration-related aggregates and endocytic probes. Surprisingly, the Bone Morphogenetic Protein (BMP) signaling pathway emerged as a strong modulator. Prion uptake was increased by transcriptional activation of the BMPR1B, BMPR2 and ACVRL1 receptors, by the BMP effector SMAD1 and by exposure to BMP ligands. Conversely, prion uptake was reduced by activation of the BMP inhibitor SMAD6. Pharmacological inhibition of BMP signaling by the antagonistic ligand noggin and by the BMP kinase inhibitor dorsomorphin decreased prion internalization, reduced the number of prion-carrying cells, and suppressed the accumulation of proteinase-resistant prion protein in a panel of chronically infected human cell lines. Hence, cell-autonomous and non-autonomous BMP signaling components regulate prion uptake, and their manipulation provides a framework for interfering with the early steps of prion propagation.

neuroscience↗

bioRxiv2025

Structure-function relationship of alpha-synuclein fibrillar polymorphs derived from distinct synucleinopathies

The aggregation of the protein alpha-synuclein (Syn) is a common feature of multiple neurodegenerative diseases collectively called synucleinopathies, for which the pathobiology is not well understood. The different phenotypic characteristics of the synucleinopathies Parkinsons disease (PD), Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA) have been proposed to originate from the distinct structures adopted by Syn in its amyloid forms. Here, using covalent labeling and limited proteolysis coupled to mass spectrometry (LiP-MS) in vitro and in situ within neuronal cells and directly in native patient brain homogenates, we show that pathogenic Syn from distinct synucleinopathies (PD, DLB and MSA) are structurally different. Further, we found that fibrillar structural differences are associated with different fibril interactomes and neuronal responses. We discovered disease-specific ubiquitination patterns and turnover profiles for pathogenic Syn species, detected molecular pathways responding specifically to the uptake of different Syn fibrillar polymorphs, and identified a subset of the involved proteins as candidate direct interactors of Syn. In particular, components of the Ubiquitin-proteasomal System (UPS), including E3 ubiquitin ligases, chaperones, and Deubiquitinating proteins, showed disease/polymorph-specific interaction patterns, possibly accounting for different resistance of patient-derived Syn fibrils to degradation. Genetic modulation with CRISPR-based tools showed that members of the UPS degradation pathway (three E3 ligases: UBE3A, TRIM25, HUWE1 and the AAA+ ATPase VCP) reduced Syn inclusions, in a strain-specific manner. LiP-MS also identified sets of proteins with altered protease susceptibility in postmortem brain homogenates of PD, DLB, and MSA patients. These sets were largely disease-specific and included proteins altered in cells treated with fibrils derived from patients with the matching disease. Our findings provide insight into cellular processes involved in the accumulation and turnover of Syn pathogenic aggregates in PD, DLB and MSA in a disease specific manner and constitutes a resource of potential novel drug targets in these synucleinopathies.

systems biology↗

bioRxiv2025

Large-scale bidirectional arrayed genetic screens identify OXR1 and EMC4 as modifiers of α-synuclein aggregation

In Parkinsons disease and other synucleinopathies, -synuclein (-Syn) misfolds and forms Ser129-phosphorylated aggregates (pSyn129). The factors controlling this process are largely unknown. Here, we used arrayed CRISPR-mediated gene activation and ablation to discover new pSyn129 modulators. Using quadruple-guide RNAs (qgRNAs) and Cas9, or an inactive Cas9 version fused to a synthetic transactivator, we ablated 2304 and activated 2428 human genes related to mitochondrial, trafficking and motility function in HEK293 cells. After exposure of cells to -Syn fibrils, pSyn129 signals were recorded by high-throughput fluorescence microscopy and aggregates were identified by image analysis. We found that pSyn129 was increased by activating the mitochondrial protein OXR1, which decreased ATP levels and altered the mitochondrial membrane potential. Instead, pSyn129 was reduced by ablation of the endoplasmic reticulum (ER)-associated protein EMC4, which enhanced ER-driven autophagic flux and lysosomal clearance. OXR1 activation preferentially modulated cellular reactions to fibrils derived from multiple system atrophy (MSA) patients, whereas EMC4 ablation broadly reduced pSyn129 across diverse -Syn polymorphs. These findings were confirmed in human iPSC-derived cortical and dopaminergic neurons, where OXR1 preferentially promoted somatic aggregation and EMC4 reduced both somatic and neuritic aggregates. These results uncover previously unrecognized roles for OXR1 and EMC4 in -Syn aggregation, thereby broadening our mechanistic understanding of synucleinopathies.

neuroscience↗

bioRxiv2025

aDISCO: A Broadly Applicable Method for 3D Microscopy of Archival Paraffin-Embedded Human Tissues

Human surgery and autopsy specimens are routinely stored as formalin-fixed paraffin-embedded (FFPE) tissue blocks. Diagnoses are based on microscopic examination of two-dimensional sections. Good clinical practice requires that samples be retained for decades, thus giving rise to vast archives of healthy and diseased tissues. While tissue clearing and whole-mount microscopy enable 3D analysis, FFPE human tissue blocks are often unsuitable for clearing and immunolabeling due to their large size, extensive cross-linking, and wax embedding. Here, we introduce archival DISCO (aDISCO), a versatile and robust clearing method designed to overcome these challenges. aDISCO achieves complete clearing and immunolabeling of large samples stored for 15 years or more. We applied aDISCO to human brain, spinal cord, peripheral nerve, skin, muscle, heart, kidney, liver, spleen, colon, and lung, using a broad range of antibodies. To investigate the clinical usefulness of quantitative 3D histology by aDISCO, we performed a case study of focal cortical dysplasia, a neurodevelopmental disease causing epilepsy. Using deep-learning-based analysis, we found disrupted cortical layering and both focal and global neuronal density variations in FCD, features that are likely to be overlooked by conventional histology. In summary, aDISCO delivers large datasets suitable for deep-learning-based processing, enabling the detection of subtle and sparse pathologies in large archival human tissue specimens.

bioengineering↗

bioRxiv2025

Gpnmb Defines a Phagocytic State of Microglia Linked to Neuronal Loss in Prion Disease

Neurodegenerative conditions can induce the region-specific emergence of cell states relevant to their pathogenesis. To identify such phenomena, we generated a spatiotemporal transcriptomic atlas of mice infected with the RML prion strain. Thalamus and cerebellum experienced severe neuronal loss, developed intense microgliosis and, starting from 30 weeks post-inoculation, accumulated a novel microglial subpopulation characterized by strong expression of Glycoprotein non-metastatic melanoma protein B (Gpnmb). Elevated GPNMB levels were detected in the cerebrospinal fluid of sCJD patients, suggesting its possible usefulness as a biomarker of disease progression. The transcriptional profile of Gpnmb+ microglia reflected a state of enhanced phagocytic activity with upregulation of genes associated with lysosomal function, including vacuolar ATPase V0 domain subunit d2 (Atp6v0d2) and Galectin-3 (Lgals3). In microglia-like murine BV2 cells, Gpnmb upregulation was induced by soluble find-me signals released during apoptosis, but not by apoptotic bodies or prion accumulation. Likewise, human iPSC-derived microglia showed marked upregulation of GPNMB when co-cultured with apoptotic human neurons. Gpnmb ablation impaired the ability of BV2 cells to clear apoptotic cells, underscoring its role in maintaining microglial phagocytosis. Our findings define Gpnmb microglia as a distinct, apoptosis-driven phagocytic state, linking neuronal loss to microglial activation and positioning it as a key regulator of microglial responses to prion propagation.

neuroscience↗

bioRxiv2024

TFAP2C and HNRNPK control mTOR cell metabolism and prion propagation

Heterogeneous Nuclear Ribonucleoprotein K (hnRNP K) is a limiting factor for prion propagation. However, little is known about the function of hnRNP K except that it is essential to cell survival. Here, we performed a synthetic-viability CRISPR ablation screen to identify epistatic interactors of HNRNPK. We found that deletion of Transcription Factor AP-2{gamma} (TFAP2C) suppressed the death of hnRNP K-depleted LN-229 and U-251 MG cells, whereas its overexpression hypersensitized cells to hnRNP K loss. HNRNPK ablation decreased cellular ATP, downregulated genes related to lipid and glucose metabolism, and enhanced autophagy. Co-occurrent deletion of TFAP2C reversed these effects, restoring transcriptional balance and alleviating energy deficiency. We linked HNRNPK and TFAP2C interaction to mTOR signaling, observing that HNRNPK ablation inhibited mTORC1 activity through downregulation of mTOR and Rptor, while TFAP2C overexpression enhanced mTORC1 downstream functions. In prion-infected cells, TFAP2C activation reduced prion levels and countered the increased prion propagation caused by HNRNPK suppression. Short-term pharmacological inhibition of mTOR also elevated prion levels and partially mimicked the effects of HNRNPK silencing. Our study identifies TFAP2C as a genetic interactor of HNRNPK, implicates their roles in mTOR metabolic regulation, and establishes a causative link between these activities and prion propagation.

cell biology↗

bioRxiv2024

Quantitative 3D histochemistry reveals region-specific amyloid-β reduction by the antidiabetic drug netoglitazone

A hallmark of Alzheimers disease (AD) is the extracellular aggregation of toxic amyloid-beta (A{beta}) peptides in form of plaques. Here, we identify netoglitazone, an antidiabetic compound previously tested in humans, as an A{beta} aggregation antagonist. Netoglitazone improved cognition and reduced microglia activity in a mouse model of AD. Using quantitative whole-brain three-dimensional histology (Q3D), we precisely identified brain regions where netoglitazone reduced the number and size of A{beta} plaques. We demonstrate the utility of Q3D in preclinical drug evaluation for AD by providing a high-resolution brain-wide view of drug efficacy. Applying Q3D has the potential to improve pre-clinical drug evaluation by providing information that can help identify mechanisms leading to brain region-specific drug efficacy. Significance statementAlzheimers disease (AD) is the most prevalent neurodegenerative disease. Its primary symptom is progressive cognitive decline, which impairs executive brain functions and deprives patients of their autonomy in life. Experimental and clinical evidence points to the critical pathophysiological role of the amyloid-beta (A{beta}) peptide. Despite some limited successes in AD immunotherapy targeting A{beta}, AD is still incurable. Here, we use an innovative pipeline for accurate whole-brain measurements of A{beta} load to test the efficacy of the antidiabetic compound, netoglitazone. We found that netoglitazone decreases A{beta} burden in certain brain areas but not in others. Region-specific assessment of anti-A{beta} efficacy may be useful in the development of effective drugs against Alzheimers disease.

neuroscience↗

bioRxiv2024

Direct and indirect regulation of β- glucocerebrosidase by the transcription factors USF2 and ONECUT2

Mutations in the GBA gene, which encodes the lysosomal enzyme {beta}-glucocerebrosidase (GCase), are the most prevalent genetic susceptibility factor for Parkinsons disease (PD). However, only approximately 20% of carriers develop the disease, suggesting the presence of genetic modifiers influencing the risk of developing PD in the presence of GBA mutations. Here we screened 1,634 human transcription factors (TFs) for their effect on GCase activity in cell lysates of the human glioblastoma line LN-229, into which we introduced the pathogenic GBA L444P variant via adenine base editing. Using a novel arrayed CRISPR activation library, we uncovered 11 TFs as regulators of GCase activity. Among these, activation of MITF and TFEC increased lysosomal GCase activity in live cells, while activation of ONECUT2 and USF2 decreased it. Conversely, ablating USF2 increased GBA mRNA and led to enhanced levels of GCase protein and activity. While MITF, TFEC, and USF2 affected GBA transcription, ONECUT2 was found to control GCase trafficking by modulating the guanine exchange factors PLEKHG4 and PLEKHG4B. Hence, our study provides a systematic approach to identifying modulators of GCase activity, expands the transcriptional landscape of GBA regulation, and deepens our understanding of the mechanisms involved in influencing GCase activity.

molecular biology↗

bioRxiv2024

α-Synuclein strain propagation is independent of cellular prion protein expression in transgenic mice

The cellular prion protein, PrPC, has been postulated to function as a receptor for -synuclein, potentially facilitating cell-to-cell spreading and/or toxicity of -synuclein aggregates in neurodegenerative disorders such as Parkinsons disease. To test this hypothesis, we compared the propagation behavior of two different -synuclein aggregate strains in M83 transgenic mice that either expressed or did not express PrPC. Following intracerebral inoculation with the S or NS strain, the presence of PrPC had minimal influence on -synuclein strain-specified attributes such as the kinetics of disease progression, the extent of cerebral -synuclein deposition, selective targeting of specific brain regions and cell types, the morphology of induced -synuclein deposits, and the structural fingerprints of protease-resistant -synuclein aggregates. Likewise, there were no appreciable differences in disease manifestation between PrPC-expressing and PrPC-lacking M83 mice following intraperitoneal inoculation of the S strain. Interestingly, intraperitoneal inoculation with the NS strain resulted in two distinct disease phenotypes, indicative of -synuclein strain evolution, but this was also independent of PrPC expression. Overall, these results suggest that PrPC plays at most a minor role in the propagation, neuroinvasion, and evolution of -synuclein strains. Thus, other putative receptors or cell-to-cell propagation mechanisms may play a larger role in the spread of -synuclein aggregates during disease.

neuroscience↗

bioRxiv2024

Involvement of the cellular prion protein in seeding and spreading of sarkosyl-derived fractions of Alzheimer's disease in Prnp mutant mice and in the P301S transgenic tauopathy mice model

The natural cellular prion protein is known to play several roles during development and adult brain. Far from its pathological roles in prionopathies, the non-pathogenic cellular prion protein has been described as a receptor for several amyloid in oligomeric and prefibrillar forms. For some amyloids, specific domains of the protein play a crucial role in modulating amyloids cellular uptake and seeding properties. In most studies, the functions and the role of putative amyloid receptors have been analyzed by using brain extracts derived from human neurodegenerative patients. Another strategy has been to modify the genetic dosage of the natural prion protein in genetic models of different diseases. In this study, we take advantage of both approaches to examine whether this protein plays a role in the seeding and spreading of pathogenic tau. Our results point to a role of the natural prion protein in the emergence of pathogenic tau in a mouse model overexpressing the mutation P301S of the human tau gene. In contrast, its role is minor when sarkosyl-derived brain samples of Alzheimers disease are used. In fact, our results indicate that the use of this type of sample is not adequate to determine the role of a putative receptor in tau seeding and spreading.

neuroscience↗

bioRxiv2023

Skeletal-Muscle Glutamine Synthase is Upregulated in Preclinical Prion Diseases

In prion diseases, aggregates of misfolded prion protein (PrPSc) accumulate not only in the brain but also in extraneural organs. This raises the question whether prion-specific pathologies arise also extraneurally. Here we sequenced mRNA transcripts in skeletal muscle, spleen and blood of prion-inoculated mice at eight timepoints during disease progression. We detected gene-expression changes in all three organs, with skeletal muscle showing the most consistent alterations. The glutamate-ammonia ligase (GLUL) gene exhibited uniform upregulation in skeletal muscles of mice infected with three distinct scrapie prion strains (RML, ME7, and 22L) and in victims of human sporadic Creutzfeldt-Jakob disease. GLUL dysregulation was accompanied by changes in glutamate/glutamine metabolism, leading to reduced glutamate levels in skeletal muscle. None of these changes were observed in skeletal muscle of humans with amyotrophic lateral sclerosis, Alzheimers disease, or dementia with Lewy bodies, suggesting that they are specific to prion diseases. These findings reveal an unexpected metabolic dimension of prion infections and point to a potential role for GLUL dysregulation in the glutamate/glutamine metabolism in prion-affected skeletal muscle.

neuroscience↗