Biology subjects

Sudderth, J.

Publications and source records attributed to Sudderth, J..

6 recordsLinked to original sources

bioRxiv2025

Hyper-Glycosylation as a Central Metabolic Driver of Alzheimers Disease

Alzheimers disease (AD) is a neurodegenerative disorder characterized by devastating degenerative decline. Metabolic disruptions are widely observed, yet their involvement in the molecular etiology of AD remains underexplored. Utilizing spatial metabolomics, lipidomics, and glycomics in both mouse models and human post-mortem samples, we identified a hyper-glycosylation phenotype as a hallmark of AD. To investigate the underlying mechanisms and whether the observed effect was a driver of the observed decline, we developed an advanced spatial isotopic tracing pulse-chase method to study the dynamics of N-linked glycans. Our analysis revealed enhanced glycan biosynthesis in AD mouse models. Based on these findings, we performed genetic and dietary interventions to modulate glycan biosynthesis. Genetic knockdown of glycan biosynthetic enzymes ameliorated the hyper-glycosylation and improved cognitive and behavioral outcomes in AD mice. In contrast, oral glucosamine supplementation drove hyper-glycosylation and exacerbated cognitive and behavioral deficits. To assess the clinical relevance of these findings, we conducted a retrospective analysis of a large population of patients with mild cognitive impairment (MCI), AD, and Alzheimers Disease Related Dementias (ADRD) stratified by glucosamine use, leveraging electronic health records. Consistently, glucosamine supplementation was associated with increased mortality in AD and ADRD patient cohorts, and significantly elevated progression from MCI to AD compared to age-matched controls. Collectively, our findings establish hyper-glycosylation as a pathological driver of AD and highlight glycan metabolism as an actional target in the fight against AD.

neuroscience↗

bioRxiv2025

L-2-hydroxyglutarate impairs neuronal differentiation through epigenetic activation of MYC expression

High levels of L- and D-2-hydroxyglutarate, the reduced forms of -ketoglutarate (KG), are implicated in human neurodevelopmental disorders and cancer. Both enantiomers exert effects on epigenetics by modulating a family of KG-dependent dioxygenases involved in histone, DNA and RNA demethylation. L-2HG dehydrogenase (L2HGDH) converts L-2HG to KG. Its deficiency is a rare, autosomal recessive inborn error of metabolism (IEM) characterized by systemic elevations of L-2HG, progressive neurological disability and a high risk of malignancy in the brain. The mechanisms behind these aberrations are unknown. Here we used an isogenic, patient-derived induced pluripotent stem cell (iPSC) system to study the impact of L2HGDH deficiency on neural progenitor cell (NPC) function and neuronal differentiation. We demonstrate that L2HGDH deficiency causes accumulation of L-2HG, NPC hyperproliferation, increased clonogenicity, excessive growth, and defective neuronal differentiation in 2D cultures and cortical spheroids. Editing the L2HGDH locus to wild-type reverses these effects. Blocking L-2HG accumulation in NPCs with a glutaminase inhibitor also induces neuronal differentiation. L-2HG-dependent inhibition of KDM5 histone demethylases leads to widespread retention of H3K4me2 and H3K4me3, markers of active gene expression. These marks are prominently elevated at the MYC locus in L2HGDH-deficient cells, and consequently cells express high MYC both in 2D culture and in many distinct cell types within cortical spheroids. Although thousands of loci display altered histone methylation, genetically or pharmacologically normalizing MYC is sufficient to completely reverse defective neuronal differentiation. These data indicate that the primary metabolic disturbance in an iPSC IEM model activates the MYC oncogene, favoring stem cell self-renewal and suppressing lineage commitment to neurons.

genetics↗

bioRxiv2023

An interactive web application for exploring human plasma and fibroblast metabolomics data from patients with inborn errors of metabolism

Metabolomic profiling is instrumental in understanding the systemic and cellular impact of inborn errors of metabolism (IEMs), monogenic disorders caused by pathogenic genomic variants in genes involved in metabolism. This study encompasses untargeted metabolomics analysis of plasma from 474 individuals and fibroblasts from 67 subjects, incorporating healthy controls, patients with 65 different monogenic diseases, and numerous undiagnosed cases. We introduce a web application designed for the in-depth exploration of this extensive metabolomics database. The application offers a user-friendly interface for data review, download, and detailed analysis of metabolic deviations linked to IEMs at the level of individual patients or groups of patients with the same diagnosis. It also provides interactive tools for investigating metabolic relationships and offers comparative analyses of plasma and fibroblast profiles. This tool emphasizes the metabolic interplay within and across biological matrices, enriching our understanding of metabolic regulation in health and disease. As a resource, the application provides broad utility in research, offering novel insights into metabolic pathways and their alterations in various disorders.

bioinformatics↗

bioRxiv2023

Mitochondrial metabolism in primary and metastatic human kidney cancers

Most kidney cancers display evidence of metabolic dysfunction1-4 but how this relates to cancer progression in humans is unknown. We used a multidisciplinary approach to infuse 13C-labeled nutrients during surgical tumour resection in over 70 patients with kidney cancer. Labeling from [U-13C]glucose varies across cancer subtypes, indicating that the kidney environment alone cannot account for all metabolic reprogramming in these tumours. Compared to the adjacent kidney, clear cell renal cell carcinomas (ccRCC) display suppressed labelling of tricarboxylic acid (TCA) cycle intermediates in vivo and in organotypic slices cultured ex vivo, indicating that suppressed labeling is tissue intrinsic. Infusions of [1,2-13C]acetate and [U-13C]glutamine in patients, coupled with respiratory flux of mitochondria isolated from kidney and tumour tissue, reveal primary defects in mitochondrial function in human ccRCC. However, ccRCC metastases unexpectedly have enhanced labeling of TCA cycle intermediates compared to primary ccRCCs, indicating a divergent metabolic program during ccRCC metastasis in patients. In mice, stimulating respiration in ccRCC cells is sufficient to promote metastatic colonization. Altogether, these findings indicate that metabolic properties evolve during human kidney cancer progression, and suggest that mitochondrial respiration may be limiting for ccRCC metastasis but not for ccRCC growth at the site of origin.

cancer biology↗

bioRxiv2021

Clinically-relevant T cell expansion protocols activate distinct cellular metabolic programs and phenotypes

Ex vivo expansion conditions used to generate T cells for immunotherapy are thought to adopt metabolic phenotypes that impede therapeutic efficacy in vivo. The comparison of five different culture media used for clinical T cell expansion revealed unique optima based on different output variables including proliferation, differentiation, function, activation and mitochondrial phenotypes. T cells adapted their metabolism to match their media expansion condition as shown by glucose and glutamine uptake, and patterns of glucose isotope labeling. However, adoption of these metabolic phenotypes was uncoupled to T cell function. Furthermore, T cell products cultured in ascites from ovarian cancer patients displayed suppressed mitochondrial activity and function irrespective of the ex vivo expansion media. In one case, culturing in ascites resulted in increased glucose uptake which was insufficient to rescue T cell function. Thus, ex vivo T cell expansion conditions have profound impacts on metabolism and function.

immunology↗

bioRxiv2019

METABOLIC DIVERSITY IN HUMAN NON-SMALL CELL LUNG CANCER CELLS

Intermediary metabolism in cancer cells is regulated by diverse cell-autonomous processes including signal transduction and gene expression patterns arising from specific oncogenotypes and cell lineages. Although it is well established that metabolic reprogramming is a hallmark of cancer, we lack a full view of the diversity of metabolic programs in cancer cells and an unbiased assessment of the associations between metabolic pathway preferences and other cell-autonomous processes. Here we quantified over 100 metabolic features, mostly from 13C enrichment of molecules from central carbon metabolism, in over 80 non-small cell lung cancer (NSCLC) cell lines cultured under identical conditions. Because these cell lines were extensively annotated for oncogenotype, gene expression, protein expression and therapeutic sensitivity, the resulting database enables the user to uncover new relationships between metabolism and these orthogonal processes.

cancer biology↗