Genetic and Transcriptomic Profiles of Inflammation in Neurodegenerative Diseases: Alzheimer, Parkinson, Creutzfeldt-Jakob and Tauopathies

González, Irene López; Garcia‐Esparcia, Paula; Llorens, Franc; Ferrer, Isidre

doi:10.3390/ijms17020206

Cited by 82 publications

(52 citation statements)

References 201 publications

(210 reference statements)

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“…Specifically, one study drew on prior literature evidence of inflammation and perturbation of the immune system, which is characteristic of AD, PD and Creutzfeldt–Jakob disease, to find transcriptomic overlaps. Using this approach, López González et al (2016) found overlaps between cytokines and the mediators of the immune response in all three diseases, as well as additional overlaps between AD and PD characterized by inflammatory markers in the blood and serum (López González et al 2016). …”

Section: Shared Gene Expression Signaturesmentioning

confidence: 99%

Shared mechanisms among neurodegenerative diseases: from genetic factors to gene networks

Arneson

Zhang

Yang

et al. 2018

J Genet

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Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis are pressing health concerns in modern societies for which effective therapies are still lacking. Recent high-throughput genomic technologies have enabled genome-scale, multidimensional investigations to facilitate a better understanding of the underlying mechanisms and the identification of novel targets. Here we review the molecular insights gained through such studies, and compare the similarities and differences between neurodegenerative diseases revealed by systems genomics and gene network modelling approaches. We focus specifically on the shared mechanisms at multiple molecular scales ranging from genetic factors to gene expression to network-level features of gene regulation, and whenever possible also point out mechanisms that distinguish one disease from another. Our review sets the stage for similar genome wide inspection in the future on shared/distinct features of neurodegenerative diseases at the levels of cellular, proteomic or epigenomic signatures, and how these features may interact to determine the progression and treatment response of different diseases afflicting the same individual.

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Section: Shared Gene Expression Signaturesmentioning

confidence: 99%

Shared mechanisms among neurodegenerative diseases: from genetic factors to gene networks

Arneson

Zhang

Yang

et al. 2018

J Genet

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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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“…It is feasible that alterations in protein homeostasis and oxidative stress could underlie the appearance of reactive astrogliosis observed in different brain areas of malin knock-out ( Epm2b −/− ) mice [25, 26]. Microglia activation and neuroinflammatory responses are currently observed in most neurodegenerative diseases and they are determinants in the pathogenesis of these processes [27–30]. However, very little is known about inflammatory responses and most particularly about gene modulation of cytokines and mediators of the immune response along with disease progression in LD.…”

Section: Introductionmentioning

confidence: 99%

Inflammation in Lafora Disease: Evolution with Disease Progression in Laforin and Malin Knock-out Mouse Models

et al. 2016

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Lafora progressive myoclonus epilepsy (Lafora disease, LD) is a fatal rare autosomal recessive neurodegenerative disorder characterized by the accumulation of insoluble ubiquitinated polyglucosan inclusions in the cytoplasm of neurons, which is most commonly associated with mutations in two genes: EPM2A, encoding the glucan phosphatase laforin, and EPM2B, encoding the E3-ubiquitin ligase malin. The present study analyzes possible inflammatory responses in the mouse lines Epm2a−/− (laforin knock-out) and Epm2b−/− (malin knock-out) with disease progression. Increased numbers of reactive astrocytes (expressing the GFAP marker) and microglia (expressing the Iba1 marker) together with increased expression of genes encoding cytokines and mediators of the inflammatory response occur in both mouse lines although with marked genotype differences. C3ar1 and CxCl10 mRNAs are significantly increased in Epm2a−/− mice aged 12 months when compared with age-matched controls, whereas C3ar1, C4b, Ccl4, CxCl10, Il1b, Il6, Tnfα and Il10ra mRNAs are significantly up-regulated in Epm2b−/− at the same age. This is accompanied by increased protein levels of IL1-β, IL6, TNFα and Cox2 particularly in Epm2b−/− mice. The severity of inflammatory changes correlates with more severe clinical symptoms previously described in Epm2b−/− mice. These findings show for the first time increased innate inflammatory responses in a neurodegenerative disease with polyglucosan intraneuronal deposits which increase with disease progression, in a way similar to what is seen in neurodegenerative diseases with abnormal protein aggregates. These findings also point to the possibility of using anti-inflammatory agents to mitigate the degenerative process in LD.

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Genetic and Transcriptomic Profiles of Inflammation in Neurodegenerative Diseases: Alzheimer, Parkinson, Creutzfeldt-Jakob and Tauopathies

Cited by 82 publications

References 201 publications

Shared mechanisms among neurodegenerative diseases: from genetic factors to gene networks

Shared mechanisms among neurodegenerative diseases: from genetic factors to gene networks

Diversity of astroglial responses across human neurodegenerative disorders and brain aging

Inflammation in Lafora Disease: Evolution with Disease Progression in Laforin and Malin Knock-out Mouse Models

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