Metadata Analysis of Astrocytic Regulatory Compensation in SOD1-G93A Amyotrophic Lateral Sclerosis Mouse Model

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by progressive degradation of motoneurons in the central nervous system (CNS). Astrocytes are key regulators for inflammation and neuromodulatory signaling, both of which contribute to ALS. The study goal was to ascertain potential temporal changes in astrocyte-mediated neuromodulatory regulation with transgenic ALS model progression: glutamate, GTL-1, GluR1, GluR2, GABA, ChAT activity, VGF, TNF, aspartate, and IGF-1. We examine neuromodulatory changes in data aggregates from 42 peer-reviewed studies derived from transgenic ALS mixed cell cultures (neurons + astrocytes). For each corresponding experimental time point, the ratio of transgenic to wild type (WT) was found for each compound. ANOVA and a student’s t-test were performed to compare disease stages (early, post-onset, and end stage). Glutamate in transgenic SOD1-G93A mixed cell cultures does not change over time (p>0.05). GLT-1 levels were found to be decreased 23% over WT but only at end-stage (p<0.05). Glutamate receptors (GluR1, GluR2) in SOD1-G93A were not substantially different from WT, although SOD1-G93A GluR1 decreased by 21% from post-onset to end-stage (p<0.05). ChAT activity was insignificantly decreased. VGF is decreased throughout ALS (p<0.05). Aspartate is elevated by 25% in SOD1-G93A but only during end-stage (p<0.05). TNF is increased by a dramatic 362% (p<0.05). Furthermore, principal component analysis identified TNF as contributing to 55% of the data variance in the first component. Thus, TNF, which modulates astrocyte regulation via multiple pathways, could be a strategic treatment target. Overall results suggest changes in neuromodulator levels are subtle in SOD1-G93A ALS mixed cell cultures. If excitotoxicity is present as is often presumed, it could be due to ALS cells being more sensitive to small changes in neuromodulation. Hence, seemingly unsubstantial or oscillatory changes in neuromodulators could wreak havoc in ALS cells, resulting in failed microenvironment homeostasis whereby both hyperexcitability and hypoexcitability can coexist. Future work is needed to examine local, spatiotemporal neuromodulatory homeostasis and assess its functional impact in ALS.Undergraduat

Increasing Power by Sharing Information from Genetic Background and Treatment in Clustering of Gene Expression Time Series

هذا البحث يطوير طريقة تجميع جديدة تسمح لكل مجموعة لتكون بارامتريسد وفقا لما إذا كان سلوك الجينات عبر الظروف مترابطة أو غير مترابطة. من خلال تحديد الارتباط بين هذه الجينات، والمزيد من المعلومات هو كسب داخل المجموعة حول كيفية الجينات المترابطة. التصلب الجانبي الضموري (ألس) هو اضطراب عصبي لا رجعة فيه يقتل الخلايا العصبية الحركية ويؤدي إلى الموت في غضون 2-3 سنوات من بداية الأعراض. سرعة التقدم لمرضى مختلفة غير متجانسة مع تباين كبير. أظهرت الفئران المعدلة وراثيا SOD1G93A من خلفيات مختلفة (129Sv و C57) الاختلافات الظواهر ثابتة لتطور المرض. التسلسل الهرمي للعمليات الغوسية المستخدمة لتشكيل نموذجية محددة وجينات محددة التباين المشترك بين الجينات. وأظهرت هذه الدراسة حول العثور على بعض ملامح التعبير الجيني هامة ومجموعات من تعبيرات الجينات المرتبطة أو المشتركة معا من أربع مجموعات من البيانات (SOD1G93A و نتغ من 129Sv و C57 الخلفيات). وتظهر دراستنا فعالية تبادل المعلومات بين المكررات وظروف نموذج مختلفة عند النمذجة الجينات سلسلة الوقت التعبير. المزيد من الجينات إثراء تحليل النتيجة وتحليل مسار الأنطولوجيا من بعض المجموعات المحددة لمجموعة معينة قد يؤدي نحو تحديد الميزات الكامنة وراء سرعة التفاضلية تطور المرض.Clustering of gene expression time series gives insight into which genes may be co-regulated, allowing us to discern the activity of pathways in a given microarray experiment. Of particular interest is how a given group of genes varies with different conditions or genetic background. This paper develops a new clustering method that allows each cluster to be parameterised according to whether the behaviour of the genes across conditions is correlated or anti-correlated. By specifying correlation between such genes,more information is gain within the cluster about how the genes interrelate. Amyotrophic lateral sclerosis (ALS) is an irreversible neurodegenerative disorder that kills the motor neurons and results in death within 2 to 3 years from the symptom onset. Speed of progression for different patients are heterogeneous with significant variability. The SOD1G93A transgenic mice from different backgrounds (129Sv and C57) showed consistent phenotypic differences for disease progression. A hierarchy of Gaussian isused processes to model condition-specific and gene-specific temporal co-variances. This study demonstrated about finding some significant gene expression profiles and clusters of associated or co-regulated gene expressions together from four groups of data (SOD1G93A and Ntg from 129Sv and C57 backgrounds). Our study shows the effectiveness of sharing information between replicates and different model conditions when modelling gene expression time series. Further gene enrichment score analysis and ontology pathway analysis of some specified clusters for a particular group may lead toward identifying features underlying the differential speed of disease progression

Tiny microRNAs Fine-Tune Amyotrophic Lateral Sclerosis Regulation

Progressing muscle wasting and dramatic neurodegeneration of upper and lower motor neurons are the initial symptoms of amyotrophic lateral sclerosis (ALS) that eventually cause aetiology or death in quick succession. The functional mechanism of ALS is non-cell autonomous but it strongly influences on non-neural cells including microglia, astrocyte muscles and T cell. In ALS, neurodegeneration is triggered by at least four gene mutations that are not related to any classical signalling pathways, molecular mechanism or known cellular ingredients. MicroRNA is endogenous tiny non-coding RNA, which is required for fine-tuning or micromanaging protein expression post-transcriptionally. In this review, we identified numerous microRNAs and their possible targets in ALS-related genes. These microRNAs misprocess ALS-related protein-coding genes via microRNA-gene circuits. This result sheds a strong link between microRNA and ALS genes. The mechanistic insight of multiple microRNAs related to ALS is required to treat neuro-inflammation and neuro-degradation. It is proposed that the micro-regulation of multiple microRNAs is involved in generation of unique neuroprotective agent against ALS. Therefore, a classical and novel microRNA-mediated therapy might unravel an alternative strategy for ALS-related neurodegeneration. This strategy indeed implicates real promises to illustrate a unique impact for ALS cure

Amylotrophic Lateral Sclerosis-Like Motor Impairment in Prion Diseases

Neurodegenerative diseases are collective diseases that affect different parts of the brain with common or distinct disease phenotype. In almost all of the Prion diseases, motor impairments that are characterized by motor derange- ment, apathy, ataxia, and myoclonus are documented and again are shared by motor neuron diseases (MND). Proteins such as; B-Cell lymphoma 2 (BCL2), Copper chaperone for superoxide dismutase (CCS), Amyloid beta precursor protein (APP), Amyloid Precursor-Like Protein1/2 (APLP1/2), Catalase (CAT), and Stress induced phosphoprotein 1 (STIP1), are common interactomes of Prion and superoxide dismutase 1 (SOD1). Although there is no strong evi- dence to show the interaction of SOD1 and Prion, the implicated common interacting proteins indicate the potential bilateral interaction of those pro- teins in health and disease. For example, down-regulation of Heat shock pro- tein A (HSPA5), a Prion interactome, increases accumulation of misfolded SOD1 leading to MND. Loss of Cu uptake function disturbs normal function of CCS. Over-expressed proteasome subunit alpha 3 (PSMA3) could fatigue its normal function of removing misfolded proteins. Studies showed the in- crease in CAT and lipid oxidation both in Prion-knocked out animal and in catalase deficiency cases. Up regulation, down regulation or direct interaction with their interactomes are predicted molecular mechanisms by which Prion and SOD exert their effect. The loss of protective function or the gain of a novel toxic property by the principal proteins is shared in Prion and MND. Thus, it might be possible to conclude that the interplay of proteins displayed in both diseases could be a key phenomenon in motor dysfunction development

Opinion: more mouse models and more translation needed for ALS

Amyotrophic lateral sclerosis is a complex disorder most of which is 'sporadic' of unknown origin but approximately 10% is familial, arising from single mutations in any of more than 30 genes. Thus, there are more than 30 familial ALS subtypes, with different, often unknown, molecular pathologies leading to a complex constellation of clinical phenotypes. We have mouse models for many genetic forms of the disorder, but these do not, on their own, necessarily show us the key pathological pathways at work in human patients. To date, we have no models for the 90% of ALS that is 'sporadic'. Potential therapies have been developed mainly using a limited set of mouse models, and through lack of alternatives, in the past these have been tested on patients regardless of aetiology. Cancer researchers have undertaken therapy development with similar challenges; they have responded by producing complex mouse models that have transformed understanding of pathological processes, and they have implemented patient stratification in multi-centre trials, leading to the effective translation of basic research findings to the clinic. ALS researchers have successfully adopted this combined approach, and now to increase our understanding of key disease pathologies, and our rate of progress for moving from mouse models to mechanism to ALS therapies we need more, innovative, complex mouse models to address specific questions

T cell responses in amyotrophic lateral sclerosis : friends or foes?

Amyotrophic lateral sclerosis (ALS) is an idiopathic fatal neurodegenerative disease that is characterized by the loss of upper and lower motor neurons. Inflammation is widely recognized as a hallmark of this disease; however, the intricate relationship between immune biomarkers and the pathogenesis of ALS is not fully understood yet. In this multidisciplinary thesis, by integrating multiple cohorts and employing diverse research methodologies, we delved deeper into the complex interplay of immune system dynamics and its impact on the risk, progression, and outcomes of this debilitating neurodegenerative disease. Study I conducted within a longitudinal population-based cohort explored the associations between blood and urine biomarkers and the future risk of ALS and Parkinson’s disease (PD). Although increasing concentrations of leukocytes, haptoglobin, and uric acid were associated with a lower risk of PD, no statistically significant associations were noted between the studied biomarkers and the risk of future ALS diagnosis. By analyzing repeated biomarker measurements, the study described the temporal changes of these biomarkers during the two decades preceding the diagnosis of these diseases, shedding light on the dynamic nature of the immune biomarkers during disease development. While levels of leukocytes and uric acid were consistently lower in PD cases compared to controls, we did not observe any consistent differences in the studied biomarkers between ALS cases and their matched controls. Study II investigated the contribution of T cell responses to disease pathology by using flow cytometric analysis of blood and cerebrospinal fluid (CSF) samples from a cohort of newly diagnosed ALS patients. Our findings suggested that T cell phenotypes, at the time of diagnosis, have the potential to serve as predictors of disease outcomes. A high frequency of CD4+FOXP3- effector T cells in both blood and CSF was associated with poor survival, while a high frequency of activated regulatory T cells and a high ratio of activated to resting regulatory T cells in blood were associated with better survival. Additionally, phenotypic profiling of T cells proved effective in predicting disease progression rate. Furthermore, single cell transcriptomic analysis of CSF samples revealed presence of clonally expanded CD4+ and CD8+ T cells with distinct gene expression patterns, further supporting the involvement of T cell responses in ALS progression and suggesting the modulation of adaptive immunity as a potential therapeutic avenue. Study III expanded the exploration of T cell responses in ALS by studying the temporal changes of these cells following ALS diagnosis. By phenotyping T cell subtypes longitudinally in the blood and CSF of ALS patients, we highlighted the predictive value of these cells in assessing disease progression. Moreover, higher levels of certain cell types, including CD3+ and CD8+ T cells, were associated with increased mortality in the months following measurement. These findings underscore the significance of T cells in monitoring the disease course and mortality in ALS. Additionally, this thesis book emphasizes the importance of methodological approaches such as data collection and analysis. Study IV highlighted the significance of analytical choices such as cohort size, follow-up time, sampling time, and choice of confounders in the context of survival analysis in ALS and their contributions to the interpretation of results. Building upon findings in Studies II and III, where the T cell subsets did not render similar associations with the disease outcome between blood and CSF, we aimed to contrast the T cell profiles between the two biospecimens. In Study V, leveraging data from a longitudinal cohort of ALS patients, we observed a weak association between the frequency of T cell subsets in blood and CSF, suggesting that the phenotypic characteristics of T cells in blood and their subsequent associations with ALS pathological features would not necessarily reflect those of the central nervous system. In conclusion, the findings of this thesis work offer valuable insights into potential prognostic assessments and potential therapeutic interventions in ALS, as well as help advance our understanding of this devastating disease and pave the way not only for future research but also for improved patient care and management