Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Amyotrophic lateral sclerosis (ALS) is an adult-onset disease characterized by the progressive death of motoneurons and denervation of muscle fibers. To restore motor function, surviving motoneurons in partially denervated muscles typically sprout axons to reinnervate denervated endplates. However, studies on the SOD1G93A rodent models of ALS indicate that sprouting is significantly limited in fast, but not slow, twitch muscles after disease onset. This limitation hastens the rate of muscle weakness and loss of motor function. The causes of this limitation are currently unknown. Sprouting could be limited because the SOD1G93A mutation weakens motoneurons making them incapable of expanding their field of innervation. Alternatively, motoneurons may be capable of sprouting, but unable to do so due to the loss of a permissive sprouting environment. To distinguish between the two possibilities, we compared the sprouting capacity of motoneuron subtypes by partially denervating the fast twitch plantaris (composed of type IIa/IIb muscle fibers) and slow twitch soleus muscles (type I/IIa fibers) prior to disease onset and weakening in SOD1G93A and WT mice. We found that only motoneurons innervating the SOD1G93A plantaris had a limited sprouting capacity. This was correlated with the selective loss of terminal Schwann cells (TSCs) at IIb fibers and an increase in macrophage infiltration. Treating SOD1G93A mice with the tyrosine kinase inhibitor, masitinib, significantly reduced infiltration, prevented TSC loss, and increased the sprouting capacity to near normal. These results suggest that TSCs at denervated type IIb muscle fibers are aberrantly targeted by infiltrating macrophages in SOD1G93A mice, and their loss accounts, at least in part, for the compromised sprouting capacity of the largest motoneurons during early stages of ALS.
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PMID:Muscle fiber-type specific terminal Schwann cell pathology leads to sprouting deficits following partial denervation in SOD1G93A mice. 3282 89

Amyotrophic lateral sclerosis (ALS) is a devastating, fatal neuromuscular disease. Most patients die within 2 to 5 years of diagnosis. The disease stems from death of upper and lower motor neurons leading to degeneration of motor pathways and the paralytic effects of the disease. The economic cost of the disease is not clear, with estimates ranging from about $64,000 per year to $200,000. Two drugs, riluzole and edaravone, are currently FDA approved for the treatment of ALS, and each provides modest benefits in mortality and/or function. Recent developments in the understanding of the underlying pathophysiologic processes that contribute to ALS have led to the development of numerous investigational therapies, with several now in phase 3 trials. This article highlights the oral tyrosine kinase inhibitor masitinib; the antisense drug tofersen; the humanized monoclonal antibody C5 complement inhibitor ravulizumab-cwvz; and mesenchymal stem cell (MSC)-neurotrophic factor (NTF) cells, a proprietary platform that induces autologous bone marrow-derived MSCs to secrete high levels of NTFs.
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PMID:Overview of current and emerging therapies for amytrophic lateral sclerosis. 3284 Mar 32

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron loss that ultimately leads to fatal paralysis. Reducing levels or function of the tyrosine kinase, ephrin type-A receptor 4 (EphA4), has been suggested as a potential approach for slowing disease progression in ALS. Because EphA4 plays roles in embryonic nervous system development, study of constitutive knockout (KO) of EphA4 in mice is limited due to confounding phenotypes with homozygous knockout. We used a tamoxifen-inducible EphA4 conditional KO mouse to achieve strong reduction of EphA4 levels in postnatal mice to test for protective effects in the SOD1G93A model of ALS. We found that EphA4 KO in young mice, but not older adult mice, causes defects in muscle function, consistent with a prolonged postnatal role for EphA4 in adolescent muscle growth. When testing the effects of inducible EphA4 KO at different timepoints in SOD1G93A mice, we found no benefits on motor function or disease pathology, including muscle denervation and motor neuron loss. Our results demonstrate deleterious effects of reducing EphA4 levels in juvenile mice and do not provide support for the hypothesis that widespread EphA4 reduction is beneficial in the SOD1G93A mouse model of ALS.
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PMID:Inducible EphA4 knockout causes motor deficits in young mice and is not protective in the SOD1G93A mouse model of ALS. 3297 90


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