RNAseq of motor neurons with differential vulnerability to ALS isolated from the SOD1G93A mouse model of ALS
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PROVIDER: PRJNA1023517 | ENA |
REPOSITORIES: ENA
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Project description:ALS is characterised by thedegeneration of somaticmotor neurons (MNs), that control voluntary muscle, while visceral motor neurons remain preserved. Some somatic motor neurons are also relatively resilient to degeneration, including oculomotor and trochlear motor neurons that regulate eye movement.In this study we aim to investigate the longitudinal transcriptional dynamics of resistant and vulnerable MN populations in response to the SOD1G93A ALS-causative mutation. We have conducted bulk RNA sequencing of MNs isolated from the SOD1G93A mouse at presymptomatic (p56) and symptomatic (p112) stages using laser capture microdissection followed by Smart-seq2 RNA sequencing. Oculomotor and trochlear (CN3/4) MN, and visceral MNs from the vagus nucleus (CN10) represent resilient neuron groups that were analysed. MNs from the lumbar spinal cord (SC) and hypoglossal (CN12) nucleus were utilised as two vulnerable populations.
2025-07-07 | GSE244538 | GEO
Project description:Although ALS typically presents in mid to late-life, there is increasing evidence for a protracted preclinical period of motor neuron dysfunction. The goal of this study is to identify the earliest gene expression patterns in lower motor neurons that drive selective neuronal vulnerability in a mouse model of ALS. We have implemented transgenic SOD1G93A with a lower motor neuron fluorescent reporter (HB9-GFP) mice to unambiguously isolate spinal motor neurons using FACS for gene expression profiling using RNA sequencing at embryonic day (E)12.5. Data from this transcriptomic study allowed the identification of disturbance in MN homeostasis which occur at the day of birth of spinal motor neurons in SOD1G93A mice. Pathway analysis uncovered several remarkably dysregulated pathways including RNA metabolism disturbance and excitotoxicity. Our findings have the potential to reveal insights into the incipient molecular mechanisms that confer motor neuron vulnerability and therefore may highlight relevant gene targets and pathways for effective intervention in ALS.
2021-08-30 | GSE142654 | GEO
Project description:Gene expression changes in spinal motor neurons of the SOD1G93A-transgenic model for ALS after treatment with G-CSF. To gain insight into the mode of action of G-CSF, we performed gene expression profiling on isolated lumbar motor neurons from SOD1G93A mice, the most frequently studied animal model for ALS, with and without G-CSF treatment. A first group of SOD1G93A and WT mice was included in the study at week 11 of age when SOD1G93A mice present no signs of motor dysfunction but subtle signs of denervation detectable by electromyography. The second cohort of mice was treated with G-CSF or vehicle from week 11 to week 15. At the time of study completion, SOD1G93A mice presented clear motor impairment and motor neuron degeneration is documented. This design should provide information on genes altered in motor neurons of SOD1G93A mice from the clinically non-symptomatic to an early symptomatic stage, and give insight into genes influenced by G-CSF treatment. We sampled 300 motoneurons per mouse spinal cord by laser microdissection.
2014-09-15 | E-GEOD-60856 | biostudies-arrayexpress
Project description:Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive paralysis due to primary and secondary degeneration of motor neurons. Despite the incredible effort of biomedical research, no curative therapy for this disease has yet been established. Given the direct interaction with neurons through neuromuscular junction (NMJ) stabilization, skeletal muscle appears to be a primary target of ALS, causing profound alteration in its function. Here we generated the first spatial transcriptomics dataset of SOD1G93A skeletal muscle as a mouse model for ALS. Using this strategy, we identified polyamine (PA) metabolism as one of the main altered pathways in affected muscle fibers. By identifying PA balance as a key factor in fiber vulnerability during disease progression, we show that perturbation of PA balance in muscle resembles disease features observed in ALS-affected muscle. Finally, we show that restoration of PA flux rescues the muscle phenotype of SOD1G93A mice, opening new perspectives in the treatment of ALS.
2025-01-01 | GSE271011 | GEO
Project description:Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive paralysis due to primary and secondary degeneration of motor neurons. In spite of extensive biomedical research, no curative therapy has yet been established. One of the primary targets of ALS is skeletal muscle, which undergoes profound functional changes as the disease progresses. To better understand how altered innervation interferes with muscle homeostasis during disease progression, we generated the first spatial transcriptomics dataset of skeletal muscle in the SOD1G93A mouse model of ALS. Using this strategy, we identified polyamine (PA) metabolism as one of the main altered pathways in affected muscle fibers. By establishing a correlation between the vulnerability of muscle fibers and the dysregulation of this metabolic pathway, we show that disrupting polyamine homeostasis causes impairments similar to those seen in ALS muscle. Finally, we show that restoration of polyamine homeostasis rescues the muscle phenotype in SOD1G93A mice, opening new perspectives for the treatment of ALS.
2025-01-01 | GSE281403 | GEO
Project description:ALS is a uniformly fatal neurodegenerative disease in which motor neurons in the spinal cord and brain stem are selectively lost. Individual motor - groups of motor neurons innervating single muscles - show widely varying degrees of disease resistance: in the final stages of ALS, nearly all voluntary movement is lost but eye movement and eliminative and sexual functions remain relatively unimpaired. These functions are controlled by motor neurons of the oculomotor (III), trochlear (IV) and abducens (VI) nuclei in the midbrain and brainstem, and by Onuf's nucleus in the lumbosacral spinal cord, respectively. Correspondingly, in ALS autopsies the oculomotor and Onuf's nuclei are almost completely preserved. We used microarray profiling of isolated wildtype mouse motor neurons to identify genes whose expression was characteristic of both oculomotor and Onuf's nuclei but not of vulnerable lumbar spinal neurons, or vice versa. Three wild-type C57BL/6J P7 male animals were perfused with 30% sucrose, lumbosacral spinal cord and midbrain regions were rapidly recovered, embedded in OCT compound, and frozen in liquid nitrogen. 12 um-thick cryosections were mounted on RNAse-free, PEN-foil covered glass slides (Zeiss), fixed for 2 min in 100% EtOH, rinsed in 50% EtOH, stained with 1% cresyl violet for 2 min, rinsed with 50% EtOH, dehydrated in graded solutions of ethanol and air dried prior to LCM using PALM Microbeam system (Zeiss). From each animal, ~200 DL, L5, and oculomotor motor neurons were collected directly in lysis buffer. RNA was purified using Absolutely RNA, NanoPrep kit (Stratagene, La Jolla, CA). RNA integrity was assessed on the Bioanalyzer 2100 (Agilent Technologies, Santa Clara, CA). At least 1.5 ng of purified RNA was the starting material used in the WT-Ovation Pico RNA Amplification System (Nugen, San Carlos,CA) with the FL-Ovation cDNA Biotin Module V2 (Nugen) to generate labeled probe. 10 ug of biotinylated cRNA from three independent samples for each motor neuron group isolated by LCM was hybridized to on Affymetrix (Santa Clara, CA) Mouse Genome 430 2.0 Arrays. Gene ontology and pathway analysis was performed using DAVID Bioinformatics Resources 6.7 (National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD).
2013-11-15 | E-GEOD-52118 | biostudies-arrayexpress
Project description:ALS is a uniformly fatal neurodegenerative disease in which motor neurons in the spinal cord and brain stem are selectively lost. Individual motor - groups of motor neurons innervating single muscles - show widely varying degrees of disease resistance: in the final stages of ALS, nearly all voluntary movement is lost but eye movement and eliminative and sexual functions remain relatively unimpaired. These functions are controlled by motor neurons of the oculomotor (III), trochlear (IV) and abducens (VI) nuclei in the midbrain and brainstem, and by Onuf’s nucleus in the lumbosacral spinal cord, respectively. Correspondingly, in ALS autopsies the oculomotor and Onuf’s nuclei are almost completely preserved. We used microarray profiling of isolated wildtype mouse motor neurons to identify genes whose expression was characteristic of both oculomotor and Onuf’s nuclei but not of vulnerable lumbar spinal neurons, or vice versa.
2013-11-15 | GSE52118 | GEO
Project description:Gene expression changes in spinal motor neurons of the SOD1G93A-transgenic model for ALS after treatment with G-CSF. To gain insight into the mode of action of G-CSF, we performed gene expression profiling on isolated lumbar motor neurons from SOD1G93A mice, the most frequently studied animal model for ALS, with and without G-CSF treatment.
2014-09-15 | GSE60856 | GEO
Project description:Background Amyotrophic lateral sclerosis (ALS) is an age-dependent and incurable neurodegenerative disease. It is pathologically characterized by selective degeneration of motor neurons resulting in a catastrophic loss of motor function. Previous studies showed that excess copper (Cu) might have a role in ALS etiology. However, the underlying mechanism remains incompletely elucidated. Therefore, we aimed to investigate the neurotoxicity and underlying mechanism of Cu exposure in female ALS mice with SOD1G93A gene mutation. Methods After three months of treatment with low-dose Cu exposure (0.13 PPM copper chloride drinking water), the motor ability was assessed by various behavioral methods, including climbing-pole test, rotarod test, hanging endurance test, grip strength test and gait analysis. Muscle atrophy and fibrosis were evaluated by histopathology. The proliferation of astrocytes and microglia was assessed by immunohistochemical analysis. The number of motor neurons in the spinal cord was determined by Nissl staining and ChAT immunohistochemical staining. Western blotting and proteomics revealed the effect of Cu exposure on mitochondrial protein expression in mice. Results Behavioral tests showed that Cu exposure worsened motor function in SOD1G93A mice. Compared with SOD1G93A transgenic mice, there was no significant difference in the pole-climbing test after Cu exposure (P =0.6156). There were significant changes in rotarod test, hanging endurance test and grip strength test (P =0.0121; P = 0.0085; P =0.0105). At the same time, Cu exposure aggravated muscle fibrosis and the loss of spinal motor neurons (P <0.05) and was associated with neuroinflammation (P <0.05). The proteomic analysis further showed that differentially expressed proteins among wild-type mice (WT), ALS mice, and Cu-treated ALS mice were mainly involved in muscle contraction, ATP metabolic processes, immune responses, peroxisomes, mitochondrial electrons respiratory transport chain, GMP biological processes, and were co-related with disturbances in energy metabolism, which was reflected in mitochondrial dysfunction in ALS mice. In addition, Western Blot showed that Cu exposure decreased the expression of mitochondria-related proteins (P <0.05), which was consistent with the results of proteomic analysis. Conclusions In conclusion, our findings showed that Cu exposure aggravates motor dysfunction and pathological changes in ALS mice via mitochondrial dysfunction.
2023-01-29 | PXD039728 |
Project description:Mutations in the Fused in Sarcoma (FUS) gene cause familial amyotrophic lateral sclerosis (ALS), characterized by selective degeneration of spinal motor neurons (sMNs) with relative sparing of cortical neurons (CNs). The mechanisms underlying this cell-type vulnerability remain unclear. Here, we compare CNs and sMNs derived from FUS-ALS models to assess differential responses to FUS mutations. We find that CNs are less affected than sMNs in DNA damage repair, axonal organelle trafficking, and stress granule dynamics. RNA sequencing (RNA-seq) reveals distinct transcriptomic signatures, with sMNs uniquely activating DNA damage responses involving cell cycle regulators, particularly polo-like kinase 1 (PLK1). PLK1 is highly expressed in sMNs but not CNs, correlating with greater nuclear FUS loss and splicing defects in sMNs. Cross-comparison with other familial ALS RNA-seq datasets highlights PLK1 upregulation as a shared molecular feature. These findings identify intrinsic differences between CNs and sMNs in FUS-ALS and suggest PLK1 as a potential driver of sMN vulnerability.
2024-08-27 | GSE272827 | GEO