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Article ; Online: A new mutation in the Parkinson's-related FBXO7 gene impairs mitochondrial and proteasomal function.

Navarro, Elisa / Esteras, Noemí

2024

Abstract: Around 10% of Parkinson's disease (PD) cases are associated with mutations in various genes, including FBXO7, which encodes the substrate-recognition component for the Skp1-Cullin-F-box (SCF) class of ubiquitin E3 ligases that target proteins for ... ...

Abstract	Around 10% of Parkinson's disease (PD) cases are associated with mutations in various genes, including FBXO7, which encodes the substrate-recognition component for the Skp1-Cullin-F-box (SCF) class of ubiquitin E3 ligases that target proteins for proteasomal degradation. In their recent study, Al Rawi et al. characterized a new mutation in FBXO7, L250P, in a pediatric patient. Their findings reveal that the L250P mutation abolishes Fbxo7 interaction with the proteasome regulator, proteasome inhibitor 31kD (PI31), affecting proteasomal activity and the ubiquitination of some of the ligase's targets. Furthermore, the authors show that this previously undescribed mutation impairs mitochondrial function and mitophagy, emphasizing the importance of mitochondrial and proteasomal dysfunction in PD pathogenesis.
Language	English
Publishing date	2024-05-06
Publishing country	England
Document type	Journal Article
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.17155
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Article: The Cannabigerol Derivative VCE-003.2 Exerts Therapeutic Effects in 6-Hydroxydopamine-Lesioned Mice: Comparison with The Classic Dopaminergic Replacement Therapy.

Rodríguez-Carreiro, Santiago / Navarro, Elisa / Muñoz, Eduardo / Fernández-Ruiz, Javier

Brain sciences

2023 Volume 13, Issue 9

Abstract: 1) Background: A cannabigerol aminoquinone derivative, so-called VCE-003.2, has been found to behave as a neuroprotective agent (administered both i.p. and orally) in different experimental models of Parkinson's disease (PD) in mice. These effects were ... ...

Abstract	(1) Background: A cannabigerol aminoquinone derivative, so-called VCE-003.2, has been found to behave as a neuroprotective agent (administered both i.p. and orally) in different experimental models of Parkinson's disease (PD) in mice. These effects were exerted through mechanisms that involved the activation of a regulatory site within the peroxisome proliferator-activated receptor-γ (PPAR-γ). (2) Methods: We are now interested in comparing such neuroprotective potential of VCE-003.2, orally administered, with the effect of the classic dopaminergic replacement therapy with L-DOPA/benserazide in similar conditions, using 6-hydroxydopamine-lesioned mice. (3) Results: The oral administration of VCE-003.2 during 14 days at the dose of 20 mg/kg improved, as expected, the neurological status (measured in motor tests) in these mice. This correlated with a preservation of TH-labelled neurons in the substantia nigra. By contrast, the treatment with L-DOPA/benserazide (during 7 days at 2 mg/kg) was significantly less active in these experimental conditions, in concordance with their profile as a mere symptom-alleviating agent. (4) Conclusions: Our results confirmed again the therapeutic profile of VCE-003.2 in experimental PD and revealed a different and more relevant effect, as a disease modifier, compared to the classic symptom-alleviating L-DOPA treatment. This reinforces the interest in VCE-003.2 for a future clinical development in this disease.
Language	English
Publishing date	2023-08-31
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2651993-8
ISSN	2076-3425
ISSN	2076-3425
DOI	10.3390/brainsci13091272
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Article ; Online: Multi-omic insights into Parkinson's Disease: From genetic associations to functional mechanisms.

Schilder, Brian M / Navarro, Elisa / Raj, Towfique

Neurobiology of disease

2021 Volume 163, Page(s) 105580

Abstract: Genome-Wide Association Studies (GWAS) have elucidated the genetic components of Parkinson's Disease (PD). However, because the vast majority of GWAS association signals fall within non-coding regions, translating these results into an interpretable, ... ...

Abstract	Genome-Wide Association Studies (GWAS) have elucidated the genetic components of Parkinson's Disease (PD). However, because the vast majority of GWAS association signals fall within non-coding regions, translating these results into an interpretable, mechanistic understanding of the disease etiology remains a major challenge in the field. In this review, we provide an overview of the approaches to prioritize putative causal variants and genes as well as summarise the primary findings of previous studies. We then discuss recent efforts to integrate multi-omics data to identify likely pathogenic cell types and biological pathways implicated in PD pathogenesis. We have compiled full summary statistics of cell-type, tissue, and phentoype enrichment analyses from multiple studies of PD GWAS and provided them in a standardized format as a resource for the research community (https://github.com/RajLabMSSM/PD_omics_review). Finally, we discuss the experimental, computational, and conceptual advances that will be necessary to fully elucidate the effects of functional variants and genes on cellular dysregulation and disease risk.
MeSH term(s)	Genetic Predisposition to Disease ; Genome-Wide Association Study ; Genomics ; Humans ; Parkinson Disease/genetics ; Polymorphism, Single Nucleotide ; Quantitative Trait Loci
Language	English
Publishing date	2021-12-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1211786-9
ISSN	1095-953X ; 0969-9961
ISSN (online)	1095-953X
ISSN	0969-9961
DOI	10.1016/j.nbd.2021.105580
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Article ; Online: Central Activation of Alpha7 Nicotinic Signaling Attenuates LPS-Induced Neuroinflammation and Sickness Behavior in Adult but Not in Aged Animals.

Navarro, Elisa / Norden, Diana M / Trojanowski, Paige J / Godbout, Jonathan P / López, Manuela G

Molecules (Basel, Switzerland)

2021 Volume 26, Issue 8

Abstract: We previously reported that lipopolysaccharide (LPS) challenge caused microglial-mediated neuroinflammation and sickness behavior that was amplified in aged mice. As α7 nAChRs are implicated in the "Cholinergic anti-inflammatory pathway", we aimed to ... ...

Abstract	We previously reported that lipopolysaccharide (LPS) challenge caused microglial-mediated neuroinflammation and sickness behavior that was amplified in aged mice. As α7 nAChRs are implicated in the "Cholinergic anti-inflammatory pathway", we aimed to determine how α7 nAChR stimulation modulates microglial phenotype in an LPS-induced neuroinflammation model in adult and aged mice. For this, BALB/c mice were injected intraperitoneally with LPS (0.33 mg/kg) and treated with the α7 nAChR agonist PNU282987, using different administration protocols. LPS challenge reduced body weight and induced lethargy and social withdrawal in adult mice. Peripheral (intraperitoneal) co-administration of the α7 nAChR agonist PNU282987 with LPS, attenuated body weight loss and sickness behavior associated with LPS challenge in adult mice, and reduced microglial activation with suppression of IL-1β and TNFα mRNA levels. Furthermore, central (intracerebroventricular) administration of the α7 nAChR agonist, even 2 h after LPS injection, attenuated the decrease in social exploratory behavior and microglial activation induced by peripheral administration of LPS, although this recovery was not achieved if activation of α7 nAChRs was performed peripherally. Finally, we observed that the positive results of central activation of α7 nAChRs were lost in aged mice. In conclusion, we provide evidence that stimulation of α7 nAChR signaling reduces microglial activation in an in vivo LPS-based model, but this cholinergic-dependent regulation seems to be dysfunctional in microglia of aged mice.
MeSH term(s)	Age Factors ; Animals ; Behavior, Animal/drug effects ; Benzamides/pharmacology ; Bridged Bicyclo Compounds/pharmacology ; Central Nervous System Diseases/etiology ; Central Nervous System Diseases/metabolism ; Central Nervous System Diseases/physiopathology ; Cytokines/metabolism ; Disease Models, Animal ; Disease Susceptibility ; Illness Behavior/drug effects ; Inflammation/etiology ; Inflammation/metabolism ; Inflammation/physiopathology ; Inflammation Mediators/metabolism ; Lipopolysaccharides/adverse effects ; Mice ; Nicotinic Agonists/pharmacology ; Signal Transduction/drug effects ; alpha7 Nicotinic Acetylcholine Receptor/agonists ; alpha7 Nicotinic Acetylcholine Receptor/metabolism
Chemical Substances	Benzamides ; Bridged Bicyclo Compounds ; Cytokines ; Inflammation Mediators ; Lipopolysaccharides ; Nicotinic Agonists ; PNU-282987 ; alpha7 Nicotinic Acetylcholine Receptor
Language	English
Publishing date	2021-04-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules26082107
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Article ; Online: Endocannabinoid-Binding Receptors as Drug Targets.

Gómez-Cañas, María / Rodríguez-Cueto, Carmen / Satta, Valentina / Hernández-Fisac, Inés / Navarro, Elisa / Fernández-Ruiz, Javier

Methods in molecular biology (Clifton, N.J.)

2022 Volume 2576, Page(s) 67–94

Abstract: Cannabis plant has been used from ancient times with therapeutic purposes for treating human pathologies, but the identification of the cellular and molecular mechanisms underlying the therapeutic properties of the phytocannabinoids, the active compounds ...

Abstract	Cannabis plant has been used from ancient times with therapeutic purposes for treating human pathologies, but the identification of the cellular and molecular mechanisms underlying the therapeutic properties of the phytocannabinoids, the active compounds in this plant, occurred in the last years of the past century. In the late 1980s and early 1990s, seminal studies demonstrated the existence of cannabinoid receptors and other elements of the so-called endocannabinoid system. These G protein-coupled receptors (GPCRs) are a key element in the functions assigned to endocannabinoids and appear to serve as promising pharmacological targets. They include CB
MeSH term(s)	Cannabinoids ; Cannabis ; Endocannabinoids ; Humans ; Peroxisome Proliferator-Activated Receptors ; Receptor, Cannabinoid, CB2 ; Receptors, Cannabinoid ; Receptors, G-Protein-Coupled
Chemical Substances	Cannabinoids ; Endocannabinoids ; Peroxisome Proliferator-Activated Receptors ; Receptor, Cannabinoid, CB2 ; Receptors, Cannabinoid ; Receptors, G-Protein-Coupled
Language	English
Publishing date	2022-09-24
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-2728-0_6
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Article ; Online: Tensor decomposition of stimulated monocyte and macrophage gene expression profiles identifies neurodegenerative disease-specific trans-eQTLs.

Ramdhani, Satesh / Navarro, Elisa / Udine, Evan / Efthymiou, Anastasia G / Schilder, Brian M / Parks, Madison / Goate, Alison / Raj, Towfique

PLoS genetics

2020 Volume 16, Issue 2, Page(s) e1008549

Abstract: Recent human genetic studies suggest that cells of the innate immune system have a primary role in the pathogenesis of neurodegenerative diseases. However, the results from these studies often do not elucidate how the genetic variants affect the biology ... ...

Abstract	Recent human genetic studies suggest that cells of the innate immune system have a primary role in the pathogenesis of neurodegenerative diseases. However, the results from these studies often do not elucidate how the genetic variants affect the biology of these cells to modulate disease risk. Here, we applied a tensor decomposition method to uncover disease associated gene networks linked to distal genetic variation in stimulated human monocyte and macrophage gene expression profiles. We report robust evidence that some disease associated genetic variants affect the expression of multiple genes in trans. These include a Parkinson's disease locus influencing the expression of genes mediated by a protease that controls lysosomal function, and Alzheimer's disease loci influencing the expression of genes involved in type 1 interferon signaling, myeloid phagocytosis, and complement cascade pathways. Overall, we uncover gene networks in induced innate immune cells linked to disease associated genetic variants, which may help elucidate the underlying biology of disease.
MeSH term(s)	Alzheimer Disease/genetics ; Alzheimer Disease/immunology ; Cell Line ; Chromosome Mapping ; Datasets as Topic ; Gene Expression Profiling ; Gene Regulatory Networks/immunology ; Genetic Predisposition to Disease ; Genetic Variation/immunology ; Genome-Wide Association Study ; Humans ; Immunity, Innate/genetics ; Interferon-gamma/immunology ; Lipopolysaccharides/immunology ; Macrophages/immunology ; Macrophages/metabolism ; Models, Genetic ; Monocytes/immunology ; Monocytes/metabolism ; Oligonucleotide Array Sequence Analysis ; Parkinson Disease/genetics ; Parkinson Disease/immunology ; Quantitative Trait Loci/immunology
Chemical Substances	Lipopolysaccharides ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2020-02-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1008549
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Article ; Online: Nrf2-ARE pathway: An emerging target against oxidative stress and neuroinflammation in neurodegenerative diseases.

Buendia, Izaskun / Michalska, Patrycja / Navarro, Elisa / Gameiro, Isabel / Egea, Javier / León, Rafael

Pharmacology & therapeutics

2016 Volume 157, Page(s) 84–104

Abstract: Neurodegenerative diseases (NDDs) are predicted to be the biggest health concern in this century and the second leading cause of death by 2050. The main risk factor of these diseases is aging, and as the aging population in Western societies is ... ...

Abstract	Neurodegenerative diseases (NDDs) are predicted to be the biggest health concern in this century and the second leading cause of death by 2050. The main risk factor of these diseases is aging, and as the aging population in Western societies is increasing, the prevalence of these diseases is augmenting exponentially. Despite the great efforts to find a cure, current treatments remain ineffective or have low efficacy. Increasing lines of evidence point to exacerbated oxidative stress, mitochondrial dysfunction and chronic neuroinflammation as common pathological mechanisms underlying neurodegeneration. We will address the role of the nuclear factor E2-related factor 2 (Nrf2) as a potential target for the treatment of NDDs. The Nrf2-ARE pathway is an intrinsic mechanism of defence against oxidative stress. Nrf2 is a transcription factor that induces the expression of a great number of cytoprotective and detoxificant genes. There are many evidences that highlight the protective role of the Nrf2-ARE pathway in neurodegenerative conditions, as it reduces oxidative stress and neuroinflammation. Therefore, the Nrf2 pathway is being increasingly considered a therapeutic target for NDDs. Herein we will review the deregulation of the Nrf2 pathway in different NDDs and the recent studies with Nrf2 inducers as "proof-of-concept" for the treatment of those devastating pathologies.
MeSH term(s)	Animals ; Humans ; Inflammation/metabolism ; NF-E2-Related Factor 2/genetics ; NF-E2-Related Factor 2/metabolism ; Neurodegenerative Diseases/metabolism ; Oxidative Stress ; Response Elements ; Signal Transduction
Chemical Substances	NF-E2-Related Factor 2
Language	English
Publishing date	2016-01
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	194735-7
ISSN	1879-016X ; 0163-7258
ISSN (online)	1879-016X
ISSN	0163-7258
DOI	10.1016/j.pharmthera.2015.11.003
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Zs.A 1183: Show issues

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Article ; Online: Sequential activation of microglia and astrocyte cytokine expression precedes increased Iba-1 or GFAP immunoreactivity following systemic immune challenge.

Norden, Diana M / Trojanowski, Paige J / Villanueva, Emmanuel / Navarro, Elisa / Godbout, Jonathan P

Glia

2016 Volume 64, Issue 2, Page(s) 300–316

Abstract: Activation of the peripheral immune system elicits a coordinated response from the central nervous system. Key to this immune to brain communication is that glia, microglia, and astrocytes, interpret and propagate inflammatory signals in the brain that ... ...

Abstract	Activation of the peripheral immune system elicits a coordinated response from the central nervous system. Key to this immune to brain communication is that glia, microglia, and astrocytes, interpret and propagate inflammatory signals in the brain that influence physiological and behavioral responses. One issue in glial biology is that morphological analysis alone is used to report on glial activation state. Therefore, our objective was to compare behavioral responses after in vivo immune (lipopolysaccharide, LPS) challenge to glial specific mRNA and morphological profiles. Here, LPS challenge induced an immediate but transient sickness response with decreased locomotion and social interaction. Corresponding with active sickness behavior (2-12 h), inflammatory cytokine mRNA expression was elevated in enriched microglia and astrocytes. Although proinflammatory cytokine expression in microglia peaked 2-4 h after LPS, astrocyte cytokine, and chemokine induction was delayed and peaked at 12 h. Morphological alterations in microglia (Iba-1(+)) and astrocytes (GFAP(+)), however, were undetected during this 2-12 h timeframe. Increased Iba-1 immunoreactivity and de-ramified microglia were evident 24 and 48 h after LPS but corresponded to the resolution phase of activation. Morphological alterations in astrocytes were undetected after LPS. Additionally, glial cytokine expression did not correlate with morphology after four repeated LPS injections. In fact, repeated LPS challenge was associated with immune and behavioral tolerance and a less inflammatory microglial profile compared with acute LPS challenge. Overall, induction of glial cytokine expression was sequential, aligned with active sickness behavior, and preceded increased Iba-1 or GFAP immunoreactivity after LPS challenge.
MeSH term(s)	Animals ; Astrocytes/metabolism ; Astrocytes/pathology ; Brain/immunology ; Brain/pathology ; Calcium-Binding Proteins/metabolism ; Cytokines/metabolism ; Disease Models, Animal ; Exploratory Behavior/physiology ; Glial Fibrillary Acidic Protein/metabolism ; Inflammation/metabolism ; Lipopolysaccharides ; Mice, Inbred BALB C ; Microfilament Proteins/metabolism ; Microglia/metabolism ; Microglia/pathology ; Motor Activity/physiology ; RNA, Messenger/metabolism
Chemical Substances	Aif1 protein, mouse ; Calcium-Binding Proteins ; Cytokines ; Glial Fibrillary Acidic Protein ; Lipopolysaccharides ; Microfilament Proteins ; RNA, Messenger ; glial fibrillary astrocytic protein, mouse
Language	English
Publishing date	2016-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	639414-0
ISSN	1098-1136 ; 0894-1491
ISSN (online)	1098-1136
ISSN	0894-1491
DOI	10.1002/glia.22930
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Zs.A 2345: Show issues

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Article ; Online: Transcriptome deregulation of peripheral monocytes and whole blood in GBA-related Parkinson's disease.

Molecular neurodegeneration

2022 Volume 17, Issue 1, Page(s) 52

Abstract: Background: Genetic mutations in beta-glucocerebrosidase (GBA) represent the major genetic risk factor for Parkinson's disease (PD). GBA participates in both the endo-lysosomal pathway and the immune response, two important mechanisms involved in the ... ...

Abstract	Background: Genetic mutations in beta-glucocerebrosidase (GBA) represent the major genetic risk factor for Parkinson's disease (PD). GBA participates in both the endo-lysosomal pathway and the immune response, two important mechanisms involved in the pathogenesis of PD. However, modifiers of GBA penetrance have not yet been fully elucidated. Methods: We characterized the transcriptomic profiles of circulating monocytes in a population of patients with PD and healthy controls (CTRL) with and without GBA variants (n = 23 PD/GBA, 13 CTRL/GBA, 56 PD, 66 CTRL) and whole blood (n = 616 PD, 362 CTRL, 127 PD/GBA, 165 CTRL/GBA). Differential expression analysis, pathway enrichment analysis, and outlier detection were performed. Ultrastructural characterization of isolated CD14+ monocytes in the four groups was also performed through electron microscopy. Results: We observed hundreds of differentially expressed genes and dysregulated pathways when comparing manifesting and non-manifesting GBA mutation carriers. Specifically, when compared to idiopathic PD, PD/GBA showed dysregulation in genes involved in alpha-synuclein degradation, aging and amyloid processing. Gene-based outlier analysis confirmed the involvement of lysosomal, membrane trafficking, and mitochondrial processing in manifesting compared to non-manifesting GBA-carriers, as also observed at the ultrastructural levels. Transcriptomic results were only partially replicated in an independent cohort of whole blood samples, suggesting cell-type specific changes. Conclusions: Overall, our transcriptomic analysis of primary monocytes identified gene targets and biological processes that can help in understanding the pathogenic mechanisms associated with GBA mutations in the context of PD.
MeSH term(s)	Glucosylceramidase/genetics ; Glucosylceramidase/metabolism ; Heterozygote ; Humans ; Monocytes/metabolism ; Mutation/genetics ; Parkinson Disease/metabolism ; Transcriptome
Chemical Substances	Glucosylceramidase (EC 3.2.1.45)
Language	English
Publishing date	2022-08-17
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2244557-2
ISSN	1750-1326 ; 1750-1326
ISSN (online)	1750-1326
ISSN	1750-1326
DOI	10.1186/s13024-022-00554-8
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Article ; Online: Genetic analysis of the human microglial transcriptome across brain regions, aging and disease pathologies.

Nature genetics

2022 Volume 54, Issue 1, Page(s) 4–17

Abstract: Microglia have emerged as important players in brain aging and pathology. To understand how genetic risk for neurological and psychiatric disorders is related to microglial function, large transcriptome studies are essential. Here we describe the ... ...

Abstract	Microglia have emerged as important players in brain aging and pathology. To understand how genetic risk for neurological and psychiatric disorders is related to microglial function, large transcriptome studies are essential. Here we describe the transcriptome analysis of 255 primary human microglial samples isolated at autopsy from multiple brain regions of 100 individuals. We performed systematic analyses to investigate various aspects of microglial heterogeneities, including brain region and aging. We mapped expression and splicing quantitative trait loci and showed that many neurological disease susceptibility loci are mediated through gene expression or splicing in microglia. Fine-mapping of these loci nominated candidate causal variants that are within microglia-specific enhancers, finding associations with microglial expression of USP6NL for Alzheimer's disease and P2RY12 for Parkinson's disease. We have built the most comprehensive catalog to date of genetic effects on the microglial transcriptome and propose candidate functional variants in neurological and psychiatric disorders.
MeSH term(s)	Aging/genetics ; Aging/metabolism ; Alzheimer Disease/metabolism ; Atlases as Topic ; Brain/metabolism ; Datasets as Topic ; Female ; Gene Expression Profiling ; Genetic Heterogeneity ; Genetic Predisposition to Disease ; Humans ; Male ; Microglia/metabolism ; Parkinson Disease/metabolism ; Quantitative Trait Loci ; RNA Splicing ; Transcriptome
Language	English
Publishing date	2022-01-06
Publishing country	United States
Document type	Journal Article ; Meta-Analysis ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1108734-1
ISSN	1546-1718 ; 1061-4036
ISSN (online)	1546-1718
ISSN	1061-4036
DOI	10.1038/s41588-021-00976-y
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Zs.A 3613: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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