In particular, we assessed the impact of MTHFR as rate-limiting enzyme in DNA methylation pathways, which modulates cerebellar neurotransmission and motor neuron atrophy.
These findings identify Stasimon dysfunction induced by SMN deficiency as an upstream driver of distinct cellular cascades that lead to synaptic loss and motor neuron degeneration, revealing a dual contribution of Stasimon to motor circuit pathology in SMA.
Mutations in the ALS19 gene lead to the reduced autophosphorylation capacity of the ErbB4 protein upon stimulation with NRG-1, suggesting that the disruption of the NRG-ErbB4 pathway causes motor neuron degeneration.
CHIT1 levels were elevated in patients with a higher number of regions displaying motor neuron degeneration (one vs three regions: 4248 vs 13 518 pg/mL, p = 0.0075).
We observed that mtSOD1 directly induced oligodendrocyte degeneration by disrupting the myelin sheath and downregulating monocarboxylate transporter 1 (MCT1), thereby causing spinal motor neuron degeneration.
Mutations in the ALS19 gene lead to the reduced autophosphorylation capacity of the ErbB4 protein upon stimulation with NRG-1, suggesting that the disruption of the NRG-ErbB4 pathway causes motor neuron degeneration.
Motor neuron degeneration and activation of neuroinflammatory cells, astrocytes, and microglia, were independent of MLKL expression in SOD1<sup>G93A</sup> mice.
Our study demonstrates that vascular regression occurs before motor neuron degeneration in FUS (1-359) mice, and highlights that heterogeneity in responses to novel ALS therapeutics can already be detected in preclinical mouse models of ALS.This article has an associated First Person interview with the joint first authors of the paper.
Using protein MS, we identified potential coordinating components of the ATP7A<sup>T994I</sup>-p97 complex, including NSFL1 cofactor (NSF1C or p47) that may be relevant to the pathophysiology and clinical effects associated with ATP7A<sup>T994I</sup> Our study represents the first report of p97/VCP binding to a UBX domain that is not normally exposed, resulting in an aberrant protein-protein interaction leading to motor neuron degeneration.
Finally, overexpressing miR126-5p is sufficient to transiently rescue axon degeneration and NMJ disruption both <i>in vitro</i> and <i>in vivo</i> Thus, we demonstrate a novel mechanism underlying ALS pathology, in which alterations in miR126-5p facilitate a non-cell-autonomous mechanism of motor neuron degeneration in ALS.<b>SIGNIFICANCE STATEMENT</b> Despite some progress, currently no effective treatment is available for amyotrophic lateral sclerosis (ALS).
Muscle-restricted nuclear receptor interaction protein knockout causes motor neuron degeneration through down-regulation of myogenin at the neuromuscular junction.
Surprisingly, human CCL2 delivered also plays a key role in preventing motor neuron degeneration in vitro and after spinal cord trauma in vivo, with a significant improvement of the motor performance of the rodent SCI models.