Dataset Information

Caudal-Rostral Progression of Alpha Motoneuron Degeneration in the SOD1^G93A Mouse Model of Amyotrophic Lateral Sclerosis.

ABSTRACT: Mice with transgenic expression of human SOD1^G93A are a widely used model of ALS, with a caudal-rostral progression of motor impairment. Previous studies have quantified the progression of motoneuron (MN) degeneration based on size, even though alpha (α-) and gamma (γ-) MNs overlap in size. Therefore, using molecular markers and synaptic inputs, we quantified the survival of α-MNs and γ-MNs at the lumbar and cervical spinal segments of 3- and 4-month SOD1^G93A mice, to investigate whether there is a caudal-rostral progression of MN death. By 3 months, in the cervical and lumbar spinal cord, there was α-MN degeneration with complete γ-MN sparing. At 3 months, the cervical spinal cord had more α-MNs per ventral horn than the lumbar spinal cord in SOD1^G93A mice. A similar spatial trend of degeneration was observed in the corticospinal tract, which remained intact in the cervical spinal cord at 3- and 4- months of age. These findings agree with the corticofugal synaptopathy model that α-MNs and CST of the lumbar spinal cord are more susceptible to degeneration in SOD1^G93A mice. Hence, there is a spatial and temporal caudal-rostral progression of α-MN and CST degeneration in SOD1^G93A mice.

SUBMITTER: Kirby AJ

PROVIDER: S-EPMC9137889 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Caudal-Rostral Progression of Alpha Motoneuron Degeneration in the SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis.

Kirby Alastair J AJ Palmer Thomas T Mead Richard J RJ Ichiyama Ronaldo M RM Chakrabarty Samit S

Antioxidants (Basel, Switzerland) 20220517 5

Mice with transgenic expression of human SOD1G93A are a widely used model of ALS, with a caudal-rostral progression of motor impairment. Previous studies have quantified the progression of motoneuron (MN) degeneration based on size, even though alpha (α-) and gamma (γ-) MNs overlap in size. Therefore, using molecular markers and synaptic inputs, we quantified the survival of α-MNs and γ-MNs at the lumbar and cervical spinal segments of 3- and 4-month SOD1G93A mice, to inves ...[more]

PMID: 35624847

Similar Datasets

Project description:BackgroundInnate neuroimmune dysfunction is a pathobiological feature of amyotrophic lateral sclerosis (ALS). However, links, if any, between disease and adaptive immunity are poorly understood. Thus, the role of T cell immunity in disease was investigated in human G93A superoxide dismutase 1 (SOD1) transgenic (Tg) mice and subsequently in ALS patients.Methods and findingsQuantitative and qualitative immune deficits in lymphoid cell and T cell function were seen in G93A-SOD1 Tg mice. Spleens of Tg animals showed reductions in size, weight, lymphocyte numbers, and morphological deficits at terminal stages of disease compared to their wild-type (Wt) littermates. Spleen sizes and weights of pre-symptomatic Tg mice were unchanged, but deficits were readily seen in T cell proliferation coincident with increased annexin-V associated apoptosis and necrosis of lymphocytes. These lymphoid deficits paralleled failure of Copolymer-1 (COP-1) immunization to affect longevity. In addition, among CD4(+) T cells in ALS patients, levels of CD45RA(+) (naïve) T cells were diminished, while CD45RO(+) (memory) T cells were increased compared to age-matched caregivers. In attempts to correct mutant SOD1 associated immune deficits, we reconstituted SOD1 Tg mice with unfractionated naïve lymphocytes or anti-CD3 activated CD4(+)CD25(+) T regulatory cells (Treg) or CD4(+)CD25(-) T effector cells (Teff) from Wt donor mice. While naive lymphocytes failed to enhance survival, both polyclonal-activated Treg and Teff subsets delayed loss of motor function and extended survival; however, only Treg delayed neurological symptom onset, whereas Teff increased latency between disease onset and entry into late stage.ConclusionsA profound and progressive immunodeficiency is operative in G93A-SOD1 mice and is linked to T cell dysfunction and the failure to elicit COP-1 neuroprotective immune responses. In preliminary studies T cell deficits were also observed in human ALS. These findings, taken together, suggest caution in ascribing vaccination outcomes when these animal models of human ALS are used for study. Nonetheless, the abilities to improve neurological function and life expectancy in G93A-SOD1 Tg mice by reconstitution with activated T cells do provide opportunities for therapeutic intervention.

Project description:IntroductionAmyotrophic Lateral Sclerosis (ALS) is a paralyzing, multifactorial neurodegenerative disease with limited therapeutics and no known cure. The study goal was to determine which pathophysiological treatment targets appear most beneficial.MethodsA big data approach was used to analyze high copy SOD1 G93A experimental data. The secondary data set comprised 227 published studies and 4,296 data points. Treatments were classified by pathophysiological target: apoptosis, axonal transport, cellular chemistry, energetics, neuron excitability, inflammation, oxidative stress, proteomics, or systemic function. Outcome assessment modalities included onset delay, health status (rotarod performance, body weight, grip strength), and survival duration. Pairwise statistical analysis (two-tailed t-test with Bonferroni correction) of normalized fold change (treatment/control) assessed significant differences in treatment efficacy. Cohen's d quantified pathophysiological treatment category effect size compared to "all" (e.g., all pathophysiological treatment categories combined).ResultsInflammation treatments were best at delaying onset (d = 0.42, p > 0.05). Oxidative stress treatments were significantly better for prolonging survival duration (d = 0.18, p < 0.05). Excitability treatments were significantly better for prolonging overall health status (d = 0.22, p < 0.05). However, the absolute best pathophysiological treatment category for prolonging health status varied with disease progression: oxidative stress was best for pre-onset health (d = 0.18, p > 0.05); excitability was best for prolonging function near onset (d = 0.34, p < 0.05); inflammation was best for prolonging post-onset function (d = 0.24, p > 0.05); and apoptosis was best for prolonging end-stage function (d = 0.49, p > 0.05). Finally, combination treatments simultaneously targeting multiple pathophysiological categories (e.g., polytherapy) performed significantly (p < 0.05) better than monotherapies at end-stage.DiscussionIn summary, the most effective pathophysiological treatments change as function of assessment modality and disease progression. Shifting pathophysiological treatment category efficacy with disease progression supports the homeostatic instability theory of ALS disease progression.

Dataset Information

Caudal-Rostral Progression of Alpha Motoneuron Degeneration in the SOD1^G93A Mouse Model of Amyotrophic Lateral Sclerosis.

Publications

Caudal-Rostral Progression of Alpha Motoneuron Degeneration in the SOD1<sup>G93A</sup> Mouse Model of Amyotrophic Lateral Sclerosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets