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Tytuł pozycji:

Neutral Lipid Cacostasis Contributes to Disease Pathogenesis in Amyotrophic Lateral Sclerosis.

Tytuł :
Neutral Lipid Cacostasis Contributes to Disease Pathogenesis in Amyotrophic Lateral Sclerosis.
Autorzy :
Dodge JC; Rare and Neurological Diseases Therapeutic Area .
Jensen EH; Rare and Neurological Diseases Therapeutic Area.
Yu J; Rare and Neurological Diseases Therapeutic Area.
Sardi SP; Rare and Neurological Diseases Therapeutic Area.
Bialas AR; Rare and Neurological Diseases Therapeutic Area.
Taksir TV; Global Discovery Pathology, Sanofi R+D, Framingham, Massachusetts 01701.
Bangari DS; Global Discovery Pathology, Sanofi R+D, Framingham, Massachusetts 01701.
Shihabuddin LS; Rare and Neurological Diseases Therapeutic Area.
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Źródło :
The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2020 Nov 18; Vol. 40 (47), pp. 9137-9147. Date of Electronic Publication: 2020 Oct 13.
Typ publikacji :
Journal Article
Język :
Imprint Name(s) :
Publication: Washington, DC : Society for Neuroscience
Original Publication: [Baltimore, Md.] : The Society, c1981-
References :
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Grant Information :
HHSN275200900011C United States HD NICHD NIH HHS
Contributed Indexing :
Keywords: amyotrophic lateral sclerosis; motor neuron disease
Entry Date(s) :
Date Created: 20201014 Latest Revision: 20201120
Update Code :
PubMed Central ID :
Czasopismo naukowe
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 SOD1 G93A mice, a model of ALS. Similar to ALS patients, a compensatory downregulation of cholesterol synthesis occurred in the spinal cord of SOD1 G93A 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.
(Copyright © 2020 the authors.)

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