Amyotrophic lateral sclerosis, gene deregulation in the anterior horn of the spinal cord and frontal cortex area 8: implications in frontotemporal lobar degeneration

Andrés‐Benito, Pol; Moreno, Jesús Rodríguez; Aso, Ester; Povedano, Mònica; Ferrer, Isidro

doi:10.18632/aging.101195

Cited by 65 publications

(52 citation statements)

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“…The identification numbers and names of TaqMan probes are shown in Table 2 . Probes were selected on the basis of our previous observations of inflammatory changes in the spinal cord and frontal cortex in sALS ( 7 ) together with additional markers linked to extravasation mechanisms and extracellular matrix remodeling. Mean values of two house-keeping genes, glucuronidase beta ( GUS- β) ( 30 ) and glyceraldehyde 3-phosphate dehydrogenase ( GAPDH ) ( 31 ), were used as internal controls for normalization.…”

Section: Methodsmentioning

confidence: 99%

“…Chronic inflammation plays the principal role in motor neuron demise and parallels the severity of motor neuron damage. A plethora of receptors, modulatory factors, chemokines, and anti- and pro-inflammatory cytokines are involved in this process at advanced stages of the disease ( 1 – 7 ). Inflammatory responses in the central nervous system are accompanied by modifications in blood and serum which may indicate a systemic inflammatory response in ALS ( 8 – 11 ).…”

Section: Introductionmentioning

confidence: 99%

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Inflammatory Gene Expression in Whole Peripheral Blood at Early Stages of Sporadic Amyotrophic Lateral Sclerosis

et al. 2017

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ObjectiveCharacterization of altered expression of selected transcripts linked to inflammation in the peripheral blood of sporadic amyotrophic lateral sclerosis (sALS) patients at early stage of disease to increase knowledge about peripheral inflammatory response in sALS.MethodsRNA expression levels of 45 genes were assessed by RT-qPCR in 22 sALS cases in parallel with 13 age-matched controls. Clinical and serum parameters were assessed at the same time.ResultsUpregulation of genes coding for factors involved in leukocyte extravasation (ITGB2, INPP5D, SELL, and ICAM1) and extracellular matrix remodeling (MMP9 and TIMP2), as well as downregulation of certain chemokines (CCL5 and CXC5R), anti-inflammatory cytokines (IL10, TGFB2, and IL10RA), pro-inflammatory cytokines (IL-6), and T-cell regulators (CD2 and TRBC1) was found in sALS cases independently of gender, clinical symptoms at onset (spinal, respiratory, or bulbar), progression, peripheral leukocyte number, and integrity of RNA. MMP9 levels positively correlated with age, whereas CCR5, CCL5, and TRBC1 negatively correlated with age in sALS but not in controls. Relatively higher TNFA expression levels correlate with higher creatinine kinase protein levels in plasma.ConclusionPresent findings show early inflammatory responses characterized by upregulation of factors enabling extravasation of leukocytes and extracellular matrix remodeling in blood in sALS cases, in addition to increased TNFA levels paralleling skeletal muscle damage.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inflammatory Gene Expression in Whole Peripheral Blood at Early Stages of Sporadic Amyotrophic Lateral Sclerosis

et al. 2017

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“…They are common in AD, PD, HD and ALS. Inflammatory responses are disease-, region-and stagedependent, thus largely differing in AD, tauopathies, CJD, PD, DLB and ALS (14,143,144,262,265,268,269). Several cytokines and mediators are expressed in reactive astrocytes in these diseases, although the precise localization of individual inflammatory mediators is largely unknown.…”

Section: Astrocytes and Inflammation In Neurodegenerative Diseases Wimentioning

confidence: 99%

Diversity of astroglial responses across human neurodegenerative disorders and brain aging

Ferrer

2017

Brain Pathology

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Astrogliopathy refers to alterations of astrocytes occurring in diseases of the nervous system, and it implies the involvement of astrocytes as key elements in the pathogenesis and pathology of diseases and injuries of the central nervous system. Reactive astrocytosis refers to the response of astrocytes to different insults to the nervous system, whereas astrocytopathy indicates hypertrophy, atrophy/degeneration and loss of function and pathological remodeling occurring as a primary cause of a disease or as a factor contributing to the development and progression of a particular disease. Reactive astrocytosis secondary to neuron loss and astrocytopathy due to intrinsic alterations of astrocytes occur in neurodegenerative diseases, overlap each other, and, together with astrocyte senescence, contribute to disease-specific astrogliopathy in aging and neurodegenerative diseases with abnormal protein aggregates in old age. In addition to the well-known increase in glial fibrillary acidic protein and other proteins in reactive astrocytes, astrocytopathy is evidenced by deposition of abnormal proteins such as β-amyloid, hyper-phosphorylated tau, abnormal α-synuclein, mutated huntingtin, phosphorylated TDP-43 and mutated SOD1, and PrP , in Alzheimer's disease, tauopathies, Lewy body diseases, Huntington's disease, amyotrophic lateral sclerosis and Creutzfeldt-Jakob disease, respectively. Astrocytopathy in these diseases can also be manifested by impaired glutamate transport; abnormal metabolism and release of neurotransmitters; altered potassium, calcium and water channels resulting in abnormal ion and water homeostasis; abnormal glucose metabolism; abnormal lipid and, particularly, cholesterol metabolism; increased oxidative damage and altered oxidative stress responses; increased production of cytokines and mediators of the inflammatory response; altered expression of connexins with deterioration of cell-to-cell networks and transfer of gliotransmitters; and worsening function of the blood brain barrier, among others. Increased knowledge of these aspects will permit a better understanding of brain aging and neurodegenerative diseases in old age as complex disorders in which neurons are not the only players.

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“…As for the ALS consensus novel predictions, missense variants in SYNE1 have been reported to be associated with a multisystemic neurological phenotypic spectrum that includes amyotrophic lateral sclerosis 42,43,44 . ALDH5A1 is significantly down-regulated in the spinal cord of an ALS murine model 45 while ABCA1 is among the altered genes in frontal cortex of ALS samples 46 . Finally, motor neurons in human ALS show significant abnormalities in DNMT3A, which is also over-expressed in synapses in mice with motor neuron degeneration 47 .…”

Section: Application Of Mantis-ml Predictions To Triage Results Frommentioning

confidence: 98%

Stochastic semi-supervised learning to prioritise genes from high-throughput genomic screens

Vitsios

Petrovski

2019

Preprint

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Access to large-scale genomics datasets has increased the utility of hypothesis-free genome-wide analyses that result in candidate lists of genes. Often these analyses highlight several gene signals that might contribute to pathogenesis but are insufficiently powered to reach experiment-wide significance. This often triggers a process of laborious evaluation of highly-ranked genes through manual inspection of various public knowledge resources to triage those considered sufficiently interesting for deeper investigation. Here, we introduce a novel multi-dimensional, multi-step machine learning framework to objectively and more holistically assess biological relevance of genes to disease studies, by relying on a plethora of gene-associated annotations. We developed mantis-ml to serve as an automated machine learning (AutoML) framework, following a stochastic semisupervised learning approach to rank known and novel disease-associated genes through iterative training and prediction sessions of random balanced datasets across the protein-coding exome (n=18,626 genes). We applied this framework on a range of disease-specific areas and as a generic disease likelihood estimator, achieving an average Area Under Curve (AUC) prediction performance of 0.85. Critically, to demonstrate applied utility on exome-wide association studies, we overlapped mantis-ml disease-specific predictions with data from published cohort-level association studies. We retrieved statistically significant enrichment of high mantis-ml predictions among the top-ranked genes from hypothesis-free cohort-level statistics (p<0.05), suggesting the capture of true prioritisation signals. We believe that mantis-ml is a novel easy-to-use tool to support objectively triaging gene discovery and overall enhancing our understanding of complex genotype-phenotype associations.

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Amyotrophic lateral sclerosis, gene deregulation in the anterior horn of the spinal cord and frontal cortex area 8: implications in frontotemporal lobar degeneration

Cited by 65 publications

References 100 publications

Inflammatory Gene Expression in Whole Peripheral Blood at Early Stages of Sporadic Amyotrophic Lateral Sclerosis

Inflammatory Gene Expression in Whole Peripheral Blood at Early Stages of Sporadic Amyotrophic Lateral Sclerosis

Diversity of astroglial responses across human neurodegenerative disorders and brain aging

Stochastic semi-supervised learning to prioritise genes from high-throughput genomic screens

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