19 research outputs found
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Peripheral blood gene expression reveals an inflammatory transcriptomic signature in Friedreich's ataxia patients.
Transcriptional changes in Friedreich's ataxia (FRDA), a rare and debilitating recessive Mendelian neurodegenerative disorder, have been studied in affected but inaccessible tissues-such as dorsal root ganglia, sensory neurons and cerebellum-in animal models or small patient series. However, transcriptional changes induced by FRDA in peripheral blood, a readily accessible tissue, have not been characterized in a large sample. We used differential expression, association with disability stage, network analysis and enrichment analysis to characterize the peripheral blood transcriptome and identify genes that were differentially expressed in FRDA patients (n = 418) compared with both heterozygous expansion carriers (n = 228) and controls (n = 93 739 individuals in total), or were associated with disease progression, resulting in a disease signature for FRDA. We identified a transcriptional signature strongly enriched for an inflammatory innate immune response. Future studies should seek to further characterize the role of peripheral inflammation in FRDA pathology and determine its relevance to overall disease progression
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Peripheral inflammation in neurodegenerative diseases
This thesis constitutes an exhaustive analysis of peripheral blood gene expression across a diverse set of neurodegenerative disease. The first manuscript included in the thesis focuses on the analysis of peripheral blood gene expression in Friedreich’s ataxia, a rare pediatric onset neurodegenerative disease caused by an autosomal recessive repeat expansion in the FXN gene, where the genetic basis of the disease is fully understood. The second manuscript takes a similar approach but instead focuses on neurodegenerative disorders with complex genetics and later onset, in particular Alzheimer’s disease (AD), mild cognitive impairment (MCI), and five disorders in the frontotemporal dementia (FTD) spectrum: behavioral variant FTD (bvFTD), semantic variant primary progressive aphasia (svPPA), and non-fluent variant primary progressive aphasia (nfvPPA), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). The initial focus of the project was to find specific gene expression biomarker candidates to build a biomarker panel, and to develop predictive models for disease status or severity from gene expression in blood. It became clear as the thesis progressed that both of these goals were not feasible, because expression changes in individual genes were too subtle and noisy to make viable biomarkers, and machine learning models had no predictive power for disease status or severity. However, systems level of analysis of the peripheral blood transcriptome with weighted gene co-expression network analysis (WGCNA) revealed evidence of an increased innate immune inflammatory response in monocytes and neutrophils. This inflammatory response was found to overlap strongly with microglia-expressed genes, particularly those genes found to be affected in post-mortem AD brains. Because of this overlap with microglial genes, the genes in the inflammatory response in blood are also enriched for genetic risk for AD as determined by genome wide association studies (GWAS). The remarkable similarity of this inflammatory response across a wide array of neurodegenerative diseases warrants further investigation, particularly to determine how and why inflammatory signals enter peripheral blood from the central and peripheral nervous system in the diseases and whether this inflammation is pathological or protective and should be a target for future therapeutic interventions
Peripheral inflammation in neurodegenerative diseases
This thesis constitutes an exhaustive analysis of peripheral blood gene expression across a diverse set of neurodegenerative disease. The first manuscript included in the thesis focuses on the analysis of peripheral blood gene expression in Friedreich’s ataxia, a rare pediatric onset neurodegenerative disease caused by an autosomal recessive repeat expansion in the FXN gene, where the genetic basis of the disease is fully understood. The second manuscript takes a similar approach but instead focuses on neurodegenerative disorders with complex genetics and later onset, in particular Alzheimer’s disease (AD), mild cognitive impairment (MCI), and five disorders in the frontotemporal dementia (FTD) spectrum: behavioral variant FTD (bvFTD), semantic variant primary progressive aphasia (svPPA), and non-fluent variant primary progressive aphasia (nfvPPA), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). The initial focus of the project was to find specific gene expression biomarker candidates to build a biomarker panel, and to develop predictive models for disease status or severity from gene expression in blood. It became clear as the thesis progressed that both of these goals were not feasible, because expression changes in individual genes were too subtle and noisy to make viable biomarkers, and machine learning models had no predictive power for disease status or severity. However, systems level of analysis of the peripheral blood transcriptome with weighted gene co-expression network analysis (WGCNA) revealed evidence of an increased innate immune inflammatory response in monocytes and neutrophils. This inflammatory response was found to overlap strongly with microglia-expressed genes, particularly those genes found to be affected in post-mortem AD brains. Because of this overlap with microglial genes, the genes in the inflammatory response in blood are also enriched for genetic risk for AD as determined by genome wide association studies (GWAS). The remarkable similarity of this inflammatory response across a wide array of neurodegenerative diseases warrants further investigation, particularly to determine how and why inflammatory signals enter peripheral blood from the central and peripheral nervous system in the diseases and whether this inflammation is pathological or protective and should be a target for future therapeutic interventions
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DNA Methylation Analysis Validates Organoids as a Viable Model for Studying Human Intestinal Aging.
Background & aimsThe epithelia of the intestine and colon turn over rapidly and are maintained by adult stem cells at the base of crypts. Although the small intestine and colon have distinct, well-characterized physiological functions, it remains unclear if there are fundamental regional differences in stem cell behavior or region-dependent degenerative changes during aging. Mesenchyme-free organoids provide useful tools for investigating intestinal stem cell biology in vitro and have started to be used for investigating age-related changes in stem cell function. However, it is unknown whether organoids maintain hallmarks of age in the absence of an aging niche. We tested whether stem cell-enriched organoids preserved the DNA methylation-based aging profiles associated with the tissues and crypts from which they were derived.MethodsTo address this, we used standard human methylation arrays and the human epigenetic clock as a biomarker of age to analyze in vitro-derived, 3-dimensional, stem cell-enriched intestinal organoids.ResultsWe found that human stem cell-enriched organoids maintained segmental differences in methylation patterns and that age, as measured by the epigenetic clock, also was maintained in vitro. Surprisingly, we found that stem cell-enriched organoids derived from the small intestine showed striking epigenetic age reduction relative to organoids derived from colon.ConclusionsOur data validate the use of organoids as a model for studying human intestinal aging and introduce methods that can be used when modeling aging or age-onset diseases in vitro
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Synaptic and Gene Regulatory Mechanisms in Schizophrenia, Autism, and 22q11.2 Copy Number Variant–Mediated Risk for Neuropsychiatric Disorders
Background22q11.2 copy number variants are among the most highly penetrant genetic risk variants for developmental neuropsychiatric disorders such as schizophrenia (SCZ) and autism spectrum disorder (ASD). However, the specific mechanisms through which they confer risk remain unclear.MethodsUsing a functional genomics approach, we integrated transcriptomic data from the developing human brain, genome-wide association findings for SCZ and ASD, protein interaction data, and gene expression signatures from SCZ and ASD postmortem cortex to 1) organize genes into the developmental cellular and molecular systems within which they operate, 2) identify neurodevelopmental processes associated with polygenic risk for SCZ and ASD across the allelic frequency spectrum, and 3) elucidate pathways and individual genes through which 22q11.2 copy number variants may confer risk for each disorder.ResultsPolygenic risk for SCZ and ASD converged on partially overlapping neurodevelopmental modules involved in synaptic function and transcriptional regulation, with ASD risk variants additionally enriched for modules involved in neuronal differentiation during fetal development. The 22q11.2 locus formed a large protein network during development that disproportionately affected SCZ-associated and ASD-associated neurodevelopmental modules, including loading highly onto synaptic and gene regulatory pathways. SEPT5, PI4KA, and SNAP29 genes are candidate drivers of 22q11.2 synaptic pathology relevant to SCZ and ASD, and DGCR8 and HIRA are candidate drivers of disease-relevant alterations in gene regulation.ConclusionsThis approach offers a powerful framework to identify neurodevelopmental processes affected by diverse risk variants for SCZ and ASD and elucidate mechanisms through which highly penetrant, multigene copy number variants contribute to disease risk
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Peripheral blood gene expression reveals an inflammatory transcriptomic signature in Friedreich's ataxia patients.
Transcriptional changes in Friedreich's ataxia (FRDA), a rare and debilitating recessive Mendelian neurodegenerative disorder, have been studied in affected but inaccessible tissues-such as dorsal root ganglia, sensory neurons and cerebellum-in animal models or small patient series. However, transcriptional changes induced by FRDA in peripheral blood, a readily accessible tissue, have not been characterized in a large sample. We used differential expression, association with disability stage, network analysis and enrichment analysis to characterize the peripheral blood transcriptome and identify genes that were differentially expressed in FRDA patients (n = 418) compared with both heterozygous expansion carriers (n = 228) and controls (n = 93 739 individuals in total), or were associated with disease progression, resulting in a disease signature for FRDA. We identified a transcriptional signature strongly enriched for an inflammatory innate immune response. Future studies should seek to further characterize the role of peripheral inflammation in FRDA pathology and determine its relevance to overall disease progression