Gil Martínez, Ana Luisa

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Gil Martínez, Ana Luisa

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Gil Martínez, Ana Luisa

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Ingeniería de la Información y las Comunicaciones

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Open Access
Modeling multifunctionality of genes with secondary gene co-expression networks in human brain provides novel disease insights
(Oxford University Press, 2021-03-18) Sánchez Laguna, Juan Antonio; Gil Martínez, Ana Luisa; Cisterna, Alejandro; García Ruiz, Sonia; Gómez Pascual, Alicia; Reynolds, Regina H.; Botía Blaya, Juan Antonio; Nalls, Mike; Hardy, John; Ryten, Mina; Ingeniería de la Información y las Comunicaciones; Facultades de la UMU::Facultad de Informática
Motivation Co-expression networks are a powerful gene expression analysis method to study how genes co-express together in clusters with functional coherence that usually resemble specific cell type behavior for the genes involved. They can be applied to bulk-tissue gene expression profiling and assign function, and usually cell type specificity, to a high percentage of the gene pool used to construct the network. One of the limitations of this method is that each gene is predicted to play a role in a specific set of coherent functions in a single cell type (i.e. at most we get a single for each gene). We present here GMSCA (Gene Multifunctionality Secondary Co-expression Analysis), a software tool that exploits the co-expression paradigm to increase the number of functions and cell types ascribed to a gene in bulk-tissue co-expression networks. Results We applied GMSCA to 27 co-expression networks derived from bulk-tissue gene expression profiling of a variety of brain tissues. Neurons and glial cells (microglia, astrocytes and oligodendrocytes) were considered the main cell types. Applying this approach, we increase the overall number of predicted triplets by 46.73%. Moreover, GMSCA predicts that the SNCA gene, traditionally associated to work mainly in neurons, also plays a relevant function in oligodendrocytes.
Open Access
Parkinson's disease: a short story of 200 years
(Universidad de Murcia. Departamento de Biología Celular e Histología, 2019) Cuenca, L.; Cano Fernandez, L.; Sanchez Rodrigo, C.; Estrada, C.; Fernández Villalba, Emiliano; Herrero Ezquerro, María Trinidad; Gil Martínez, Ana Luisa
After Alzheimer’s disease, Parkinson’s disease (PD) is the second most prevalent and incidental neurodegenerative disorder, affecting more than 2% of the population older than 65 years old. Since it was first described 200 years ago by Dr James Parkinson, great steps have been made in the understanding of the pathology. However, the cause(s) that initiates and perpetuates the neurodegenerative process is (are) still not clear. Thus, early diagnosis is not available, nor are there efficient therapies that can stop neurodegeneration. PD clinical features are defined by motor (like bradykinesia, resting tremor, gait impairment) and nonmotor symptoms (like constipation, apathy, fathigue, olfactory dysfunction, depression and cognitive decline) that get more severe as the disease advances. Neuropathological hallmarks comprise selective loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc) and Lewy bodies (LB) in different nuclei of the nervous system. Numerous studies have shown that these pathological features are aggravated by the confluence of other contributing factors, such as a genetic component, exposure to environmental toxins, mitochondrial dysfunction, increase of oxidative stress, calcium imbalance and chronic neuroinflammation, among others. Here, we provide a summary of the actual state of PD’s pathology, the most studied molecular mechanisms, classic and novel therapeutic strategies and diagnosis methods, especially highlighting recent advances in these 200 years
Open Access
Identification of differentially expressed genes profiles in a combined mouse model of Parkinsonism and colitis
(Nature research, ) Cuenca, L.; González Cuello, A.; Sánchez Rodrigo, C.; Parrado, A.; Vyas, S.; Herrero Ezquerro, María Trinidad; Gil Martínez, Ana Luisa; Fernández Villalba, Emiliano; Enfermería
Open Access
Regional brain iron and gene expression provide insights into neurodegeneration in Parkinson’s disease
(Oxford Univeristy Press, 2021-03-11) Thomas, George E.C.; Zarkali, Angeliki; Ryten, Mina; Shmueli, Karin; Gil Martínez, Ana Luisa; Leyland, Louis-Ann; McColgan, Peter; Acosta-Cabronero, Julio; Lees, Andrew J.; Weil, Rimona S.; Ingeniería de la Información y las Comunicaciones
The mechanisms responsible for the selective vulnerability of specific neuronal populations in Parkinson’s disease are poorly understood. Oxidative stress secondary to brain iron accumulation is one postulated mechanism. We measured iron deposition in 180 cortical regions of 96 patients with Parkinson’s disease and 35 control subjects using quantitative susceptibility mapping. We estimated the expression of 15 745 genes in the same regions using transcriptomic data from the Allen Human Brain Atlas. Using partial least squares regression, we then identified the profile of gene transcription in the healthy brain that underlies increased cortical iron in patients with Parkinson’s disease relative to controls. Applying gene ontological tools, we investigated the biological processes and cell types associated with this transcriptomic profile and identified the sets of genes with spatial expression profiles in control brains that correlated significantly with the spatial pattern of cortical iron deposition in Parkinson’s disease. Gene ontological analyses revealed that these genes were enriched for biological processes relating to heavy metal detoxification, synaptic function and nervous system development and were predominantly expressed in astrocytes and glutamatergic neurons. Furthermore, we demonstrated that the genes differentially expressed in Parkinson’s disease are associated with the pattern of cortical expression identified in this study. Our findings provide mechanistic insights into regional selective vulnerabilities in Parkinson’s disease, particularly the processes involving iron accumulation.
Open Access
CoExp: A Web Tool for the Exploitation of Co-expression Networks
(Frontiers Media SA, 2021-02-24) García-Ruiz, Sonia ; Cisterna, Alejandro; Jurado-Ruiz, Federico; Reynolds, Regina H. ; NABEC (North American Brain Expression Consortium); Cookson, Mark R.; Hardy, John ; Ryten, Mina; Gil Martínez, Ana Luisa; Botía Blaya, Juan Antonio; Ingeniería de la Información y las Comunicaciones
Gene co-expression networks are a powerful type of analysis to construct gene groupings based on transcriptomic profiling. Co-expression networks make it possible to discover modules of genes whose mRNA levels are highly correlated across samples. Subsequent annotation of modules often reveals biological functions and/or evidence of cellular specificity for cell types implicated in the tissue being studied. There are multiple ways to perform such analyses with weighted gene co-expression network analysis (WGCNA) amongst one of the most widely used R packages. While managing a few network models can be done manually, it is often more advantageous to study a wider set of models derived from multiple independently generated transcriptomic data sets (e.g., multiple networks built from many transcriptomic sources). However, there is no software tool available that allows this to be easily achieved. Furthermore, the visual nature of co-expression networks in combination with the coding skills required to explore networks, makes the construction of a web-based platform for their management highly desirable. Here, we present the CoExp Web application, a user-friendly online tool that allows the exploitation of the full collection of 109 co-expression networks provided by the CoExpNets suite of R packages. We describe the usage of CoExp, including its contents and the functionality available through the family of CoExpNets packages. All the tools presented, including the web front- and back-ends are available for the research community so any research group can build its own suite of networks and make them accessible through their own CoExp Web application. Therefore, this paper is of interest to both researchers wishing to annotate their genes of interest across different brain network models and specialists interested in the creation of GCNs looking for a tool to appropriately manage, use, publish, and share their networks in a consistent and productive manner.
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Voluntary exercise reduces plasma cortisol levels and improves transitory memory impairment in young and aged Octodon degus
(Elsevier, ) Estrada, Cristina; Cuenca, Lorena; Cano Fernández, Lorena; Sánchez Rodrigo, Consuelo; González Cuello, Ana Maria; Fernández Villalba, Emiliano; Herrero, Maria Teresa; Gil Martínez, Ana Luisa; Enfermería
Sleep deprivation (SD) has been reported to induce transient cognitive impairment in functional domains commonly affected in dementia, including memory. Indeed, sleep disturbance has been proposed as an early marker for Alzheimer’s disease (AD). SD emulates many aging-related modifications, including important memory dysfunctions possibly caused by triggers of stress such as cortisol. Although exercise is widely assumed to be beneficial for overall health, only recently has the research community focused its attention on its possible effects on brain functions such as cognition. Octodon degus (O. degus) is a recent rodent model considered suitable for the study of neurodegenerative diseases, since it spontaneously develops several histopathological hallmarks observed in AD. We aimed to uncover the interaction between stress, exercise, age and transient memory impairments after SD insult. In this study, animals had free individual access to wheels to practice voluntary exercise. The Barnes Maze (BM) task was conducted with young and aged O. degus animals after combining voluntary exercise and either normal sleep or SD. Plasma cortisol levels were measured after each condition. SD impaired hippocampus-dependent memory in both young and old animals, while cortisol levels did not significantly differ between non-SD and SD animals. However, voluntary exercise for 45 days improved the cognitive impairment caused by SD compared with the control condition. Moreover, voluntary exercise decreased plasma cortisol levels in both conditions, independently of the age.
Open Access
Comunicaciones Orales.-Lesión de la mucosa gastrointestinal exacerba la inflamación en ratones parkinsonianos
(2020-05-26) Cano, J. A.; Valiente, M.; Estrada, C.; González-Cuello, A.; Fernández, E.; Fernández-Gómez, F.; Herrero Ezquerro, María Trinidad; Gil Martínez, Ana Luisa; Facultades, Departamentos, Servicios y Escuelas::Facultades de la UMU::Facultad de Medicina
Open Access
IntroVerse: a comprehensive database of introns across human tissues
(Oxford University Press , 2022-11-18) Garcia-Ruiz, Sonia; Gustavsson, Emil K. ; Zhang, David; Reynolds, Regina H. ; Chen, Zhongbo; Fairbrother-Browne, Aine; Gil Martínez, Ana Luisa; Botía Blaya, Juan Antonio; Collado-Torres, Leonardo; Ryten, Mina; Ingeniería de la Información y las Comunicaciones; Facultades de la UMU::Facultad de Informática
Dysregulation of RNA splicing contributes to both rare and complex diseases. RNA-sequencing data from human tissues has shown that this process can be inaccurate, resulting in the presence of novel introns detected at low frequency across samples and within an individual. To enable the full spectrum of intron use to be explored, we have developed Intro- Verse, which offers an extensive catalogue on the splicing of 332,571 annotated introns and a linked set of 4,679,474 novel junctions covering 32,669 different genes. This dataset has been generated through the analysis of 17,510 human control RNA samples from 54 tissues provided by the Genotype-Tissue Expression Consortium. IntroVerse has two unique features: (i) it provides a complete catalogue of novel junctions and (ii) each novel junction has been assigned to a specific annotated intron. This unique, hierarchical structure offers multiple uses, including the identification of novel transcripts from known genes and their tissue-specific usage, and the assessment of background splicing noise for introns thought to be mis-spliced in disease states. Intro-Verse provides a user-friendly web interface and is freely available at https://rytenlab.com/browser/app/introverse.
Open Access
Urolithins: potential biomarkers of gut dysbiosis and disease stage in Parkinson's patients
(The Royal Society of Chemistry, 2022-04-28) Romo Vaquero, María; Cuenca Bermejo, Lorena; Espín de Gea, Juan Carlos; Selma García, María Victoria; Herrero Ezquerro, María Trinidad; Gil Martínez, Ana Luisa; Fernández Villalba, Emiliano; Anatomía Humana y Psicobiología
Gut microbiota alteration (gut dysbiosis) occurs during the onset and progression of Parkinson's disease. Gut dysbiosis biomarkers could be relevant to prodromal disease. Urolithins, anti-inflammatory metabolites produced from some dietary polyphenols by specific gut microbial ecologies (urolithin metabotypes), have been proposed as biomarkers of gut microbiota composition and functionality. However, this has not been explored in Parkinson's disease patients. The current study aimed to assess associations between urolithin metabotypes, gut dysbiosis and disease severity in Parkinson's disease patients. Participants (52 patients and 117 healthy controls) provided stool samples for microbiota sequencing and urine samples for urolithin profiling before and after consuming 30 g of walnuts for three days. Data on demographics, medication, disease duration and Hoehn and Yahr disease stage were collected. We observed a significant gradual increase of urolithin non-producers (metabotype-0) as the disease severity increased. The gut microbiome of metabotype-0 patients and patients with the greatest severity was characterized by a more altered bacterial composition, i.e., increased pro-inflammatory Enterobacteriaceae and reduced protective bacteria against autoimmune and inflammatory processes, including butyrate and urolithin-producing bacteria (Lachnospiraceae members and Gordonibacter). Besides, their microbiome was characterized by predictive functions of lipopolysaccharide biosynthesis and metabolism of glutathione, cysteine and methionine that could indirectly reflect the gut pro-inflammatory status. Urolithin detection in urine is a feasible, non-invasive and fast approach that can reflect gut microbiome dysbiosis and intestinal inflammation in Parkinson's disease patients. Our current study could provide novel strategies for improving diagnostics, and for preventing and treating disease progression in microbiota-based interventions.
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Electrical stimulation or MK-801 in the inferior colliculus improve motor deficits in MPTP-treated mice
(Elsevier. Science Direct, 2018-01) Melo Thomas, L; Cuenca, L; Estrada, C; Gonzalez-Cuello, A; Schwarting, RK; Herrero Ezquerro, María Trinidad; Gil Martínez, Ana Luisa; Enfermería
The inferior colliculus (IC) is an important midbrain relay station for the integration of descending and ascending auditory information. Additionally, the IC has been implicated in processing sensorimotor responses. Glutamatergic and GABAergic manipulations in the IC can improve motor deficits as demonstrated by the animal model of haloperidol-induced catalepsy. However, how the IC influences motor function remains unclear. We investigated the effects of either intracollicular deep brain stimulation (DBS) or microinjection of the glutamatergic antagonist MK-801 or the agonist NMDA in C57BL/6J mice chronically treated with saline or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). After DBS or microinjections, the mice were submitted to rotarod and open field tests, respectively. DBS in the IC was effective to increase the time spent on the rotarod in MPTP-treated mice. After unilateral microinjection of MK-801, but not NMDA, MPTP-treated mice increased the distance travelled in the open field (p < 0.05). In conclusion, intracollicular DBS or MK-801 microinjection can improve motor performance in parkinsonian mice suggesting the IC as a new and non-conventional therapeutic target in motor impairment.