Biology subjects

Monzel, A. S.

Publications and source records attributed to Monzel, A. S..

13 recordsLinked to original sources

bioRxiv2025

Electroconvulsive Therapy Induces Dopaminergic Axon Regeneration, Corticostriatal Remodeling, and Restoration of Motor Function in Parkinsonian Mice

Parkinsons disease (PD) is characterized by the progressive degeneration of midbrain dopaminergic neurons with loss of axonal dopamine neurotransmission in the dorsal striatum, leading to striatal circuit dysfunction and debilitating motor symptoms. Current therapies provide symptomatic relief but do not restore lost neuronal function. Decades of clinical observations have reported the unexpected observation that electroconvulsive therapy (ECT), a standard treatment for refractory neuropsychiatric disorders, can incidentally alleviate motor symptoms in PD patients, yet the underlying mechanisms remain unknown. Here, we report that in the unilateral 6-hydroxydopamine (6-OHDA) mouse model of PD, two weeks of repeated ECT produced robust and sustained motor recovery, with improvements in locomotion and sensorimotor asymmetry persisting for at least 30 days post-treatment. Remarkably, ECT induced dopaminergic axonal sprouting from surviving dopaminergic neurons with cell bodies located at the substantia nigra-ventral tegmental border, leading to a partial recovery of striatal dopaminergic axonal reinnervation. In striatal direct pathway spiny projection neurons (dSPNs), which exhibit pathological hyperexcitability and spine loss following dopamine depletion, ECT normalized both corticostriatal synaptic responses and spine density. Consistently, ECT upregulated gene transcripts involved in cytoskeletal remodeling while downregulating those associated with glutamatergic signaling and neuronal excitability. These changes were accompanied by a coordinated transcriptional shift toward enhanced mitochondrial anabolic capacity and energy production, including increased expression of genes involved in ATP and Coenzyme Q biosynthesis. Together, these findings demonstrate that ECT can partially restore basal ganglia circuitry following dopamine depletion and provide a basis for further study of its potential as a noninvasive, disease-modifying intervention for PD.

neuroscience↗

bioRxiv2025

A Quantitative Approach to Mapping Mitochondrial Specialization and Plasticity

Mitochondria are a diverse family of organelles with highly specialized functions. While they share common features, their molecular and functional diversity remains underexplored. Here, we introduce a quantitative pipeline to define the degree of molecular specialization among different mitochondrial phenotypes, or mitotypes. By distilling hundreds of validated mitochondrial genes into 149 biologically interpretable MitoPathway scores, this streamlined mitotyping framework enables investigators to quantify and interpret mitochondrial diversity and plasticity from transcriptomic data across a variety of natural and experimental contexts. Using this approach, we show that mouse and human multi-organ mitotypes segregate along two main axes of mitochondrial specialization, characterize robust longitudinal and perturbation-induced metabolic plasticity in cultured human fibroblasts, and resolve cell-type and single-cell mitochondrial recalibrations across the human brain and sperm developmental trajectory. Together, this framework provides a practical and extensible approach for analyzing mitochondrial specialization in complex biological systems.

cell biology↗

bioRxiv2025

Mapping the GDF15 Arm of the Integrated Stress Response in Human Cells and Tissues

Mitochondrial stress activates the integrated stress response (ISR) and triggers cell-cell communication through the secretion of the metabokine growth differentiation factor 15 (GDF15). However, the gene network underlying the ISR remains poorly defined, particularly across metabolically diverse cellular states and tissues. Using RNAseq data from fibroblasts subjected to eleven metabolic perturbations, including genetic and pharmacological mitochondrial OxPhos defects, we showed that the ISR has multiple arms and developed an ISRGDF15 index quantifying the GDF15 arm of ISR activation in human cells. The ISRGDF15 index was validated using optogenetic activation of the ISR protein kinase R (PKR) in a stable cell line, demonstrating its rapid kinetics preceding to GDF15 gene expression. We then deployed the ISRGDF15 index across 44 postmortem human tissues, reporting that the ISRGDF15 was upregulated in the heart of individuals who died of an acute cause in the emergency room, whereas it was preferentially upregulated in the brain of individuals who died as inpatients after protracted hospital stays. ISRGDF15 was also moderately, positively correlated with age across all tissues. These data highlight multiple distinct ISR pathways and clarify which genes are related to the GDF15 arm of the ISR, yielding an ISRGDF15 index that can be used to investigate tissue-specific and age-related ISR activation in both in vitro cultures and human tissues. Ultimately, we expand our knowledge of the GDF15 arm of the ISR in humans, show its inducibility by the ISR kinase PKR, and demonstrate its applicability to detect ISR activation in specific human tissues.

cell biology↗

bioRxiv2025

Immune cell mitochondrial phenotypes are largely preserved in mitochondrial diseases and do not reflect disease severity

ObjectiveTo profile immune cell mitochondrial phenotypes in mitochondrial diseases (MitoD) and evaluate how those phenotypes relate to disease manifestations or biomarkers. MethodsWe profiled mitochondrial content and OxPhos enzymatic activities in isolated monocytes, lymphocytes, neutrophils, platelets, and mixed peripheral blood mononuclear cells (PBMCs) from 37 individuals with MitoD (m.3243A>G, n=23; single, large-scale mitochondrial DNA (mtDNA) deletions, n=14) and 68 healthy women and men from the MiSBIE study. ResultsWe first confirm and quantify robust cell type differences in mitochondrial content, activities of OxPhos complexes I, II, and IV, and the mitochondrial respiratory capacity (MRC) index. In relation to MitoD, neither mitochondrial content nor OxPhos capacity were consistently affected, other than a mild monocyte-specific reduction in complex I (partially mtDNA encoded) relative to complex II (entirely nDNA encoded), consistent with the mtDNA defects examined. Relative to the large differences in cell type-specific mitochondrial phenotypes, differences in MitoD relative to controls were generally small (<25%) across mitochondrial measures. The MitoD biomarkers GDF15 and FGF21, as well as clinical disease severity measures, were most strongly related to mitochondrial abnormalities in platelets, and most weakly related to mitochondrial OxPhos capacity in lymphocytes, which are known to eliminate mtDNA defects. Finally, comparing PBMCs collected in the morning/fasted state to the afternoon/fed state following a stressful experience, we report significant time-dependent changes in mitochondrial biology over the time scale of hours. ConclusionsOverall, these results demonstrate that the dynamic and cell-type specific mitochondrial phenotypes are preserved in mitochondrial diseases and are generally unrelated to the severity of MitoD symptoms.

pathology↗

bioRxiv2024

Deciphering shared molecular dysregulation across Parkinson's disease variants using a multi-modal network-based data integration and analysis

Parkinsons disease (PD) is a progressive neurodegenerative disorder with no effective treatment. Advances in neuroscience and systems biomedicine now enable the use of complex patient-specific in vitro disease models and cutting-edge computational tools for data integration, enhancing our understanding of complex PD mechanisms. To explore common biomedical features across monogenic PD forms, we developed a knowledge graph (KG) by integrating previously published high-content imaging and RNA sequencing data of PD patient-specific midbrain organoids harbouring LRRK2-G2019S, SNCA triplication, GBA-N370S or MIRO1-R272Q mutations with publicly available biological data. Furthermore, we generated a single-cell RNA sequencing dataset of midbrain organoids derived fromidiopathic PD patients (IPD) to stratify IPD patients towards genetic forms of PD. Despite high PD heterogeneity, we found that common transcriptomic dysregulation in monogenic PD forms is reflected in IPD glial cells. In addition, dysregulation in ROBO signalling might be involved in shared pathophysiology between monogenic PD and IPD cases.

systems biology↗

bioRxiv2024

Brain-body mitochondrial distribution patterns lack coherence and point to tissue-specific and individualized regulatory mechanisms

Energy transformation capacity is generally assumed to be a coherent individual trait driven by genetic and environmental factors. This predicts that some individuals should have high and others low mitochondrial oxidative phosphorylation (OxPhos) capacity across organ systems. Here, we test this assumption using multi-tissue molecular and enzymatic activities in mice and humans. Across up to 22 mouse tissues, neither mitochondrial OxPhos capacity nor mtDNA density were correlated between tissues (median r = -0.01-0.16), indicating that animals with high mitochondrial capacity in one tissue can have low capacity in other tissues. Similarly, the multi-tissue correlation structure of RNAseq-based indices of mitochondrial gene expression across 45 tissues from 948 women and men (GTEx) showed small to moderate coherence between only some tissues (regions of the same brain), but not between brain-body tissue pairs in the same person (median r = 0.01). Mitochondrial DNA copy number (mtDNAcn) also lacked coherence across organs and tissues. Mechanistically, tissue-specific differences in mitochondrial gene expression were attributable in part to i) tissue-specific activation of canonical energy sensing pathways including the transcriptional coactivator PGC-111 and the integrated stress response (ISR), and ii) proliferative activity across tissues. Finally, we identify subgroups of individuals with high mitochondrial gene expression in some tissues (e.g., heart) but low expression in others (e.g., skeletal muscle) who display different clinical phenotypic patterns. Taken together, these data raise the possibility that tissue-specific energy sensing pathways may contribute to the idiosyncratic mitochondrial distribution patterns associated with the inter-organ heterogeneity and phenotypic diversity among individuals.

cell biology↗

bioRxiv2024

Psychobiological regulation of plasma and saliva GDF15 dynamics in health and mitochondrial diseases

Growth Differentiation Factor 15 (GDF15) is a protein that reflects mitochondrial energetic stress and is linked to physical and mental health symptoms, aging, and mortality. Here, we tested the hypothesis that GDF15 is a stress-responsive biomarker through a series of observational and experimental studies. We report four main findings. First, in the UK Biobank (n=53,026) and Framingham Heart Study (FHS) Offspring (n=3,460) cohorts, plasma GDF15 levels were elevated in individuals with symptoms of depression and anxiety. In the FHS cohort, GDF15 was also higher in participants exposed to chronic psychosocial stressors, including lower educational attainment, lower family income, and higher job strain. Second, plasma GDF15 levels in the FHS cohort correlated positively with epigenetic clocks measuring biological aging and effect sizes of GDF15 associations with psychosocial stressors were comparable to those observed for the clocks. Third, in a two-participant intensive-sampling study (n=112 days), saliva GDF15 showed a robust awakening response similar to established stress-related hormones. However, it exhibited a distinct negative pattern, peaking at waking and declining by 42-92% within 30-45 minutes. Finally, in two laboratory experiments (n=148), acute social-evaluative stress significant increased GDF15 levels in plasma and saliva within minutes. Together, these findings suggest that psychosocial stress may contribute to mitochondrial energetic stress indexed by GDF15, with implications for aging and health. This work opens new avenues for using GDF15 as a non-invasive biomarker to study the biological embedding of stress and its impact on aging trajectories. Significance statementGrowth Differentiation Factor 15 (GDF15) is a circulating protein elevated with mitochondrial energetic stress, aging, and diseases. Our findings show that GDF15 is elevated with depressive and anxiety symptoms and in those exposed to chronic psychosocial stress. Elevated plasma GDF15 also correlates with accelerated biological aging, as measured by epigenetic clocks. The effect sizes linking GDF15 to psychosocial stressors were comparable to those observed for the epigenetic clocks. Saliva GDF15 shows a robust negative awakening response characterized by elevated levels at awakening before declining within 30-45 minutes. Acute social-evaluative stress induced increase in plasma and saliva GDF15. Together, these findings suggest GDF15 can be used to study the energetic mechanisms for the biological embedding of stress across the lifespan.

physiology↗

bioRxiv2024

A Human Brain Map of Mitochondrial Respiratory Capacity and Diversity

Mitochondrial oxidative phosphorylation (OxPhos) powers brain activity1,2, and mitochondrial defects are linked to neurodegenerative and neuropsychiatric disorders3,4, underscoring the need to define the brains molecular energetic landscape5-10. To bridge the cognitive neuroscience and cell biology scale gap, we developed a physical voxelization approach to partition a frozen human coronal hemisphere section into 703 voxels comparable to neuroimaging resolution (3x3x3 mm). In each cortical and subcortical brain voxel, we profiled mitochondrial phenotypes including OxPhos enzyme activities, mitochondrial DNA and volume density, and mitochondria-specific respiratory capacity. We show that the human brain contains a diversity of mitochondrial phenotypes driven by both topology and cell types. Compared to white matter, grey matter contains >50% more mitochondria. We show that the more abundant grey matter mitochondria also are biochemically optimized for energy transformation, particularly among recently evolved cortical brain regions. Scaling these data to the whole brain, we created a backward linear regression model integrating several neuroimaging modalities11, thereby generating a brain-wide map of mitochondrial distribution and specialization that predicts mitochondrial characteristics in an independent brain region of the same donor brain. This new approach and the resulting MitoBrainMap of mitochondrial phenotypes provide a foundation for exploring the molecular energetic landscape that enables normal brain functions, relating it to neuroimaging data, and defining the subcellular basis for regionalized brain processes relevant to neuropsychiatric and neurodegenerative disorders.

neuroscience↗

bioRxiv2022

Glucocorticoid and adrenergic receptor distribution across human organs and tissues: a map for stress transduction

ObjectivePsychosocial stress is transduced into disease risk through energy-dependent release of hormones that affect target organs, tissues, and cells. The magnitude of the physiological stress responses reflects both systemic levels of these hormones and the sensitivity of target tissues to their effects. Thus, differential expression of receptors across organs likely contributes to stress transduction. Here we provide a quantitative whole-body map of glucocorticoid and adrenergic receptor expression. MethodsWe systematically examined gene expression levels for the glucocorticoid receptor (GR), - and {beta}-adrenergic receptors (AR-1B, AR-2B AR-{beta}2, and AR-{beta}3), across 55 different organs using the Human Protein Atlas dataset. We also leveraged the Human Proteome Map and MitoCarta3.0 data to examine receptor protein levels and, given the energy-dependence of the stress response, the link between stress hormone receptor density and mitochondrial pathways. Finally, we tested the functional interplay between GR activation and AR expression in living human cells. ResultsThe GR was expressed ubiquitously across all investigated organ systems. Immune tissues and cells expressed the highest GR RNA and protein levels. In contrast, AR subtypes showed lower and more localized expression patterns. Co-regulation was found between GR and AR-1B, as well as between AR-1B and AR-2B. In human fibroblasts, activating the GR selectively increased AR-{beta}2 (3.6-fold) and AR-1B (2.2-fold) expression, confirming their interaction. Consistent with the energetic cost of stress responses, GR and AR expression were positively associated with the expression of key mitochondrial pathways. ConclusionOur results provide a cartography of GR and AR expression across the human body. Tissue-specific stress hormone receptor expression patterns could make specific organ systems more responsive to the sustained, energetically expensive, neuroendocrine signaling pathways triggered by chronic psychosocial stress.

cell biology↗

bioRxiv2022

Chronic Glucocorticoid Stress Reveals Increased Energy Expenditure and Accelerated Aging as Cellular Features of Allostatic Load

Stress triggers anticipatory physiological responses that promote survival, a phenomenon termed allostasis. However, the chronic activation of energy-dependent allostatic responses results in allostatic load, a dysregulated state that predicts functional decline, accelerates aging, and increases mortality in humans. The energetic cost and cellular basis for the damaging effects of allostatic load have not been defined. Here, by longitudinally profiling three unrelated primary human fibroblast lines across their lifespan, we find that chronic glucocorticoid exposure increases cellular energy expenditure by [~]60%, along with a metabolic shift from glycolysis to mitochondrial oxidative phosphorylation (OxPhos). This state of stress-induced hypermetabolism is linked to mtDNA instability, non-linearly affects age-related cytokines secretion, and accelerates cellular aging based on DNA methylation clocks, telomere shortening rate, and reduced lifespan. Pharmacologically normalizing OxPhos activity while further increasing energy expenditure exacerbates the accelerated aging phenotype, pointing to total energy expenditure as a potential driver of aging dynamics. Together, our findings define bioenergetic and multi-omic recalibrations of stress adaptation, underscoring increased energy expenditure and accelerated cellular aging as interrelated features of cellular allostatic load.

cell biology↗

bioRxiv2021

A Multi-Omics and Bioenergetics Longitudinal Aging Dataset in Primary Human Fibroblasts with Mitochondrial Perturbations

Aging is a process of progressive change. In order to develop biological models of aging, longitudinal datasets with high temporal resolution are needed. Here we report a multi-omic longitudinal dataset for cultured primary human fibroblasts measured across their replicative lifespans. Fibroblasts were sourced from both healthy donors (n=6) and individuals with lifespan-shortening mitochondrial disease (n=3). The dataset includes cytological, bioenergetic, DNA methylation, gene expression, secreted proteins, mitochondrial DNA copy number and mutations, cell-free DNA, telomere length, and whole-genome sequencing data. This dataset enables the bridging of mechanistic processes of aging as outlined by the "hallmarks of aging", with the descriptive characterization of aging such as epigenetic age clocks. Here we focus on bridging the gap for the hallmark mitochondrial metabolism. Our dataset includes measurement of healthy cells, and cells subjected to over a dozen experimental manipulations targeting oxidative phosphorylation (OxPhos), glycolysis, and glucocorticoid signaling, among others. These experiments provide opportunities to test how cellular energetics affect the biology of cellular aging. All data are publicly available at our webtool: https://columbia-picard.shinyapps.io/shinyapp-Lifespan_Study/

cell biology↗

bioRxiv2019

Parkinson’s disease phenotypes in patient specific brain organoids are improved by HP-β-CD treatment

The etiology of Parkinsons disease (PD) is only partially understood despite the fact that environmental causes, risk factors, and specific gene mutations are contributors to the disease. Biallelic mutations in the PTEN-induced putative kinase 1 (PINK1) gene involved in mitochondrial homeostasis, vesicle trafficking, and autophagy, are sufficient to cause PD. By comparing PD patient-derived cells, we show differences in their energetic profile, imbalanced proliferation, apoptosis, mitophagy, and a reduced differentiation efficiency to dopaminergic neurons compared to control cells. Using CRISPR/Cas9 gene editing, correction of a patients point mutation ameliorated the metabolic properties and neuronal firing rates but without reversing the differentiation phenotype. However, treatment with 2-Hydroxypropyl-{beta}-Cyclodextrin (HP-{beta}-CD) increased the mitophagy capacity of neurons leading to an improved dopaminergic differentiation of patient specific neurons in midbrain organoids. In conclusion, we show that treatment with a repurposed compound is sufficient for restoring dopaminergic differentiation of PD patient-derived cells.

neuroscience↗

bioRxiv2019

Machine learning-assisted neurotoxicity prediction in human midbrain organoids

A major challenge in the field of neurodegenerative diseases is the poor translation of pre-clinical models to clinical applications. The human brain is an immensely complex structure, which makes it difficult to recapitulate its development, function and disorders. In the recent years, brain organoids derived from human induced pluripotent stem cells have risen as novel tools to study neurodegenerative diseases such as Parkinsons disease (PD). PD is a multifactorial disorder, with aging, genetics and environmental factors as key etiological elements. The majority of the PD cases are idiopathic and proposed to result from a complex interaction between genetic predisposition and environmental exposure. Consequently, the identification of potentially disease causing environmental factors is of critical importance. Organoids, as complex multi-cellular tissue proxies, are an ideal tool to study cellular response to environmental changes. However, with increasing complexity of the system, usage of quantitative tools becomes challenging. This led us to develop an automated high-content image analysis pipeline for image-based cell profiling in the organoid system. Here, we introduce a midbrain organoid system that recapitulates features of neurotoxin-induced PD, representing a platform for machine-learning-assisted prediction of neurotoxicity in high-content imaging data. This model is a valuable tool for advanced in vitro PD modeling and for the screening of putative neurotoxic compounds.

pharmacology and toxicology↗