Metabolic alterations in the absence of a detectable neuromuscular phenotype in novel genomically humanisedSOD1^A4Vmice.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: May 4, 2025

ABSTRACT Amyotrophic lateral sclerosis (ALS) caused by mutation in superoxide dismutase 1 ( SOD1 ) accounts for 15-30% of familial ALS and is typically autosomal dominant. How single base pair/amino acid changes this small protein cause neurodegeneration unknown. In North America, A4V the most common results an aggressive form ALS. Here, we present a novel genomically humanised mouse model , which Sod1 locus has been replaced human gene, with intact genomic architecture exons introns, but bearing mutation. agreement previously reported knock-in mice, phenotype mild; however, transcriptomic metabolomic profiling reveal significant dysregulation glycolysis, tricarboxylic (TCA) cycle, lipid metabolism. These suggest early bioenergetic imbalance that precedes neuromuscular impairment. Our findings support metabolic dysfunction as event pathogenesis. This freely available provides valuable tool studying progression identifying therapeutic targets pre-symptomatic treatment. SUMMARY STATEMENT study describes generation analysis revealing through integrated multi-omic analyses, characterising potential future research.

Language: Английский

Anodal tsDCS restores the structure and function of the disrupted proprioceptive Ia synapses on spinal motoneurons in the SOD1 G93A mouse model of ALS

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 6, 2024

Abstract An imbalance between cells’ intrinsic excitability and synaptic excitation levels is the basis of spinal motoneuron (MN) pathophysiology in Amyotrophic Lateral Sclerosis. Recently, a restoration deficient Ia MNs was achieved by applying acute trans-spinal direct current stimulation (tsDCS) to presymptomatic SOD1 G93A mice. Here we investigate whether two-week repeated tsDCS applied animals can provoke MN neuroplasticity reduce disease burden. Anodal, cathodal or sham polarisation 100 µA P30-P35 mice; passive membrane properties excitatory post-synaptic potential (EPSP) characteristics were investigated intracellular recordings vivo. A second cohort polarized used test impact our intervention on synapse morphology, metabolic pathways activity, markers. Anodal evoked strong increase maximal EPSPs, coupled with significant upregulation vesicular glutamate transporter GlurR4 subunits AMPA receptors at synapse. On other hand, failed induce any alteration morphology but did both peak plateau input resistance recovered abnormal paired-pulse ratio. Unexpectedly, changes electrophysiological profile not translate into alterations ctivity decrease Altogether results indicate polarity-dependent plasticity mice response tsDCS, which nevertheless appears insufficient alter dynamics. Highlights 14-days alters proprioceptive synapses mouse model ALS (depolarising) increases restores postsynaptic elements Cathodal (hyperpolarising) does Both anodal fail significantly modify cellular burden

Language: Английский