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)

Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, are commonly used in the therapy of cardiovascular diseases. Recent studies suggest that statins may induce amyotrophic lateral sclerosis (ALS) in some patients, but no pathogenic mechanism has been proposed for this association. Herein the hypothesis is proposed that statins may induce or aggravate ALS by impairing liver X receptor (LXR) signaling. The hypothesis is supported by the following observations: 1) statins inhibit the synthesis of endogenous LXR agonists, oxysterols, and decrease the expression of LXR target genes in many cells, 2) mice lacking LXRbeta exhibit sn ALS-like phenotype, 3) statins increase the concentration of plant sterols in plasma and tissues, partially by impairing LXR-dependent signaling, which results in augmented intestinal absorption and impaired biliary excretion of plant sterols, and 4) some plant sterols are toxic to motor neurons of the spinal cord, which are primarily affected in ALS patients. If this hypothesis is confirmed, LXR agonists could be used together with statins in patients predisposed to develop ALS or in those known to have the disorder to prevent motor neuron degeneration.
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PMID:Statins and ALS: the possible role of impaired LXR signaling. 2019 Jun 99

Microglia are the primary innate immune system cells in the central nervous system (CNS). They are crucial for the immunity, neurogenesis, synaptogenesis, neurotrophic support, phagocytosis of cellular debris, and maintaining the CNS integrity and homeostasis. Invasion by pathogens as well as in CNS injuries and damages results in activation of microglia known as microgliosis. The activated microglia have the capacity to release proinflammatory mediators leading to neuroinflammation. However, uncontrolled neuroinflammation can give rise to various neurological disorders (NDs), especially the neurodegenerative diseases including Parkinson's disease (PD) and related disorders, Alzheimer's disease (AD) and other dementias, multiple sclerosis (MS), Huntington's disease (HD), spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), and stroke. Statins (HMG-CoA reductase inhibitors) are among the most widely prescribed medications for the management of hypercholesterolemia worldwide. It can be used for primary prevention in healthy individuals who are at higher risk of cardiovascular and coronary heart diseases as well as the secondary prevention in patients with cardiovascular and coronary heart diseases disease. A growing body of evidence has indicated that statins have the potential to attenuate the proinflammatory mediators and subsequent NDs by controlling the microglial activation and consequent reduction in neuroinflammatory mediators. In this review, we have discussed the recent studies on the effects of statins on microglia activation and neuroinflammation.
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PMID:The effects of statins on microglial cells to protect against neurodegenerative disorders: A mechanistic review. 3184 36

Fused in sarcoma (FUS) is a predominantly nuclear multifunctional RNA/DNA-binding protein that regulates multiple aspects of gene expression. FUS mutations are associated with familial amyotrophic lateral sclerosis (fALS) and frontotemporal lobe degeneration (FTLD) in humans. At the molecular level, the mutated FUS protein is reduced in the nucleus but accumulates in cytoplasmic granules. Oligodendrocytes (OL) carrying clinically relevant FUS mutations contribute to non-cell autonomous motor neuron disease progression, consistent with an extrinsic mechanism of disease mediated by OL. Knocking out FUS globally or in neurons lead to behavioral abnormalities that are similar to those present in FTLD. In this study, we sought to investigate whether an extrinsic mechanism mediated by loss of FUS function in OL contributes to the behavioral phenotype. We have generated a novel conditional knockout (cKO) in which Fus is selectively depleted in OL (FusOL cKO). The FusOL cKO mice show increased novelty-induced motor activity and enhanced exploratory behavior, which are reminiscent of some manifestations of FTLD. The phenotypes are associated with greater myelin thickness, higher number of myelinated small diameter axons without an increase in the number of mature OL. The expression of the rate-limiting enzyme of cholesterol biosynthesis (HMGCR) is increased in white matter tracts of the FusOL cKO and results in higher cholesterol content. In addition, phosphorylation of Akt, an important regulator of myelination is increased in the FusOL cKO. Collectively, this work has uncovered a novel role of oligodendrocytic Fus in regulating myelin deposition through activation of Akt and cholesterol biosynthesis.
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PMID:Conditional depletion of Fus in oligodendrocytes leads to motor hyperactivity and increased myelin deposition associated with Akt and cholesterol activation. 3218 1

Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease characterized by motor neuron (MN) death. Lipid dysregulation manifests during disease; however, it is unclear whether lipid homeostasis is adversely affected in the in the spinal cord gray matter (GM), and if so, whether it is because of an aberrant increase in lipid synthesis. Moreover, it is unknown whether lipid dysregulation contributes to MN death. Here, we show that cholesterol ester (CE) and triacylglycerol levels are elevated several-fold in the spinal cord GM of male sporadic ALS patients. Interestingly, HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, was reduced in the spinal cord GM of ALS patients. Increased cytosolic phospholipase A2 activity and lyso-phosphatidylcholine (Lyso-PC) levels in ALS patients suggest that CE accumulation was driven by acyl group transfer from PC to cholesterol. Notably, Lyso-PC, a byproduct of CE synthesis, was toxic to human MNs in vitro Elevations in CE, triacylglycerol, and Lyso-PC were also found in the spinal cord of SOD1G93A mice, a model of ALS. Similar to ALS patients, a compensatory downregulation of cholesterol synthesis occurred in the spinal cord of SOD1G93A mice; levels of sterol regulatory element binding protein 2, a transcriptional regulator of cholesterol synthesis, progressively declined. Remarkably, overexpressing sterol regulatory element binding protein 2 in the spinal cord of normal mice to model CE accumulation led to ALS-like lipid pathology, MN death, astrogliosis, paralysis, and reduced survival. Thus, spinal cord lipid dysregulation in ALS likely contributes to neurodegeneration and developing therapies to restore lipid homeostasis may lead to a treatment for ALS.SIGNIFICANCE STATEMENT Neurons that control muscular function progressively degenerate in patients with amyotrophic lateral sclerosis (ALS). Lipid dysregulation is a feature of ALS; however, it is unclear whether disrupted lipid homeostasis (i.e., lipid cacostasis) occurs proximal to degenerating neurons in the spinal cord, what causes it, and whether it contributes to neurodegeneration. Here we show that lipid cacostasis occurs in the spinal cord gray matter of ALS patients. Lipid accumulation was not associated with an aberrant increase in synthesis or reduced hydrolysis, as enzymatic and transcriptional regulators of lipid synthesis were downregulated during disease. Last, we demonstrated that genetic induction of lipid cacostasis in the CNS of normal mice was associated with ALS-like lipid pathology, astrogliosis, neurodegeneration, and clinical features of ALS.
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PMID:Neutral Lipid Cacostasis Contributes to Disease Pathogenesis in Amyotrophic Lateral Sclerosis. 3305 52