Spinal muscular atrophy (SMA) is a pediatric genetic disorder characterized by the loss of spinal cord motor neurons. Although the mechanisms underlying motor neuron loss are not clear, current data suggest that glial cells contribute to disease pathology. We have previously found that SMA astrocytes drive microglial activation and motor neuron loss potentially through the upregulation of NFkB-mediated pro-inflammatory cytokines. In this study, we tested the ability of neutralizing C-C motif chemokine ligand 5 (CCL5) while increasing either interleukin 10 (IL-10) or IL-1 receptor antagonist (IL-1ra) to reduce the pro-inflammatory phenotype of SMA astrocytes. While IL-10 was ineffective, IL-1ra ameliorated SMA astrocyte-driven glial activation and motor neuron loss in iPSC-derived cultures in vitro. In vivo AAV5 delivered IL-1ra overexpression and miR-30 shRNA knockdown of CCL5 had modest but significant improvements on lifespan, weight gain, motor neuron number, and motor function of SMNΔ7 mice. Together these data identify IL-1ra and CCL5 as possible therapeutic targets for SMA and highlight the importance of glial-targeted therapeutics for neurodegenerative disease.
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http://dx.doi.org/10.1016/j.ymthe.2024.12.016 | DOI Listing |
Semin Respir Crit Care Med
December 2024
Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, Ohio.
Neuromuscular disorders can cause respiratory impairment by affecting the muscle fibers, neuromuscular junction, or innervation of respiratory muscles, leading to significant morbidity and mortality. Over the past few years, new disease-modifying therapies have been developed and made available for treating different neuromuscular disorders. Some of these therapies have remarkable effectiveness, resulting in the prevention and reduction of respiratory complications.
View Article and Find Full Text PDFInt J Sports Physiol Perform
December 2024
Department of Anesthesiology and Intensive Care, Akershus University Hospital, Lørenskog, Norway.
Purpose: Laboratory studies have demonstrated that manual dexterity decreases with increasing cold, which may adversely affect performance. Dexterity may be impaired by cooling of the hand, cooling of the lower motor neurons, and cognitive impairment. Wetsuits are commonly used in open-water swimming and are mandated in some situations.
View Article and Find Full Text PDFTissue Cell
December 2024
Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia.
Traumatic spinal cord injury (TSCI) is a serious medical issue where there is a loss of sensorimotor function. Current interventions continue to lack the ability to successfully enhance these conditions, therefore, it is crucial to consider alternative effective strategies. Currently, we investigated the effects of fibrin scaffold encapsulated with epigallocatechin gallate (EGCG) microspheres in the recovery of SCI in rats.
View Article and Find Full Text PDFMol Biol (Mosk)
December 2024
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991 Russia.
The process of mRNA localization in the cytoplasm involves the directed transport of mRNP particles using the microtubule system. This transport is mediated and regulated by specific factors-adaptors between mRNA molecules and microtubule motor proteins. Adaptors are a key link in the mechanism of mRNA transport, but to date their identity and functioning are mostly unknown.
View Article and Find Full Text PDFActa Neuropathol Commun
December 2024
Institute of Myology, Neuromuscular Morphology Unit, Sorbonne Université, INSERM, GHU Pitié-Salpêtrière, Paris, France.
Neuromuscular disorders (NMD) with neonatal or early infantile onset are usually severe and differ in symptoms, complications, and treatment options. The establishment of a diagnosis relies on the combination of clinical examination, morphological analyses of muscle biopsies, and genetic investigations. Here, we re-evaluated and classified a unique collection of 535 muscle biopsies from NMD infants aged 0-6 months examined over a period of 52 years.
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