A plural role for lipids in motor neuron diseases: energy, signaling and structure

Schmitt, Florent; Hussain, Ghulam; Dupuis, Luc; Loeffler, Jean‐Philippe; Henriques, Alexandre Cruz

doi:10.3389/fncel.2014.00025

Cited by 106 publications

(87 citation statements)

References 127 publications

(133 reference statements)

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“…Specifically, lipids are closely related to neurodegeneration (52,53). Although Sig-1Rs bind to certain lipids (34)(35)(36) and have been shown to partake in lipid biosynthesis (54,55), the specific physiological role arising from the Sig-1R-lipid interaction remains unknown.…”

Section: Sig-1r Controls P35 Degradation Mainly Through the Proteasomalmentioning

confidence: 99%

Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid

Tsai

Pokrass

Klauer

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Dysregulation of cyclin-dependent kinase 5 (cdk5) per relative concentrations of its activators p35 and p25 is implicated in neurodegenerative diseases. P35 has a short t ½ and undergoes rapid proteasomal degradation in its membrane-bound myristoylated form. P35 is converted by calpain to p25, which, along with an extended t ½ , promotes aberrant activation of cdk5 and causes abnormal hyperphosphorylation of tau, thus leading to the formation of neurofibrillary tangles. The sigma-1 receptor (Sig-1R) is an endoplasmic reticulum chaperone that is implicated in neuronal survival. However, the specific role of the Sig-1R in neurodegeneration is unclear. Here we found that Sig-1Rs regulate proper tau phosphorylation and axon extension by promoting p35 turnover through the receptor's interaction with myristic acid. In Sig-1R-KO neurons, a greater accumulation of p35 is seen, which results from neither elevated transcription of p35 nor disrupted calpain activity, but rather to the slower degradation of p35. In contrast, Sig-1R overexpression causes a decrease of p35. Sig-1R-KO neurons exhibit shorter axons with lower densities. Myristic acid is found here to bind Sig-1R as an agonist that causes the dissociation of Sig-1R from its cognate partner binding immunoglobulin protein. Remarkably, treatment of Sig-1R-KO neurons with exogenous myristic acid mitigates p35 accumulation, diminishes tau phosphorylation, and restores axon elongation. Our results define the involvement of Sig-1Rs in neurodegeneration and provide a mechanistic explanation that Sig-1Rs help maintain proper tau phosphorylation by potentially carrying and providing myristic acid to p35 for enhanced p35 degradation to circumvent the formation of overreactive cdk5/p25.A xons are structurally and functionally distinct protrusions of neurons that modulate neurotransmitter release and neural function. Malfunction of axonal maintenance, regeneration, and target recognition contribute to CNS disorders such as Alzheimer's disease (AD), Parkinson's disease, stroke, and spinal cord injuries (1-3). Cyclin-dependent kinase (Cdk) 5 activities within the axon play a significant role in the cytoskeletal dynamics of microtubules and actin neurofilaments (NFs), which determine axonal path and length. Specifically, cdk5 active complexes phosphorylate proteins that contribute to the stabilization or destabilization of microtubules, formation of neurofibrillary tangles, and axonal pathfinding (4-6).Cdk5 is a ubiquitously expressed enzyme; however, its activator, p35, is almost exclusively expressed in neurons (7,8). Cdk5 signaling supports neurite projection and proper neuronal migration (9-11). Dysregulation of cdk5 activity leads to hyperphosphorylation of several substrates, including NF proteins and tau, which causes the formation of neurofibrillary tangles (6, 12). Although the kinetics of cdk5 activity when in complex with p35 or p25 are the same, cdk5/p25 complexes are proposed to be responsible for neurodegenerative pathophysiology because of their longer duration o...

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Section: Sig-1r Controls P35 Degradation Mainly Through the Proteasomalmentioning

confidence: 99%

Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid

Tsai

Pokrass

Klauer

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Lipid metabolism was described as deeply involved in ALS pathophysiology [52,53]. In particular, several studies reported hyperlipidemia in patients with ALS [53][54][55][56][57], with a potential link with patient survival [53].…”

Section: Moderate Effect On Metabolismmentioning

confidence: 99%

Combined Metabolomics and Transcriptomics Approaches to Assess the IL-6 Blockade as a Therapeutic of ALS: Deleterious Alteration of Lipid Metabolism

et al. 2016

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In amyotrophic lateral sclerosis (ALS), motor neuron degeneration occurs simultaneously with systemic metabolic impairment and neuroinflammation. Playing an important role in the regulation of both phenomena, interleukin (IL)-6, a major cytokine of the inflammatory response has been proposed as a target for management of ALS. Although a pilot clinical trial provided promising results in humans, another recent preclinical study showed that knocking out the IL-6 gene in mice carrying ALS did not improve clinical outcome. In this study, we aimed to determine the relevance of the IL-6 pathway blockade in a mouse model of ALS by using a pharmacological antagonist of IL-6, a murine surrogate of tocilizumab, namely MR16-1. We analyzed the immunological and metabolic effects of IL-6 blockade by cytokine measurement, blood cell immunophenotyping, targeted metabolomics, and transcriptomics. A deleterious clinical effect of MR16-1 was revealed, with a speeding up of weight loss (p = 0.0041) and decreasing body weight (p < 0.05). A significant increase in regulatory T-cell count (p = 0.0268) and a decrease in C-X-C ligand-1 concentrations in plasma (p = 0.0479) were observed. Metabolomic and transcriptomic analyses revealed that MR16-1 mainly affected branchedchain amino acid, lipid, arginine, and proline metabolism. IL-6 blockade negatively affected body weight, despite a moderated anti-inflammatory effect. Metabolic effects of IL-6 were mild compared with metabolic disturbances observed in ALS, but a modification of lipid metabolism by

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“…Abnormal metabolism and dyslipidemia are frequently present in amyotrophic lateral sclerosis (ALS), and could be associated with the clinical outcome . The recent view is that dysmetabolism is not a mere consequence of decreased oral intake and muscle atrophy; rather, ALS is a systemic disease that affects metabolic pathways . A recent animal study suggested that the liver is the target organ in ALS, with this view being supported by the post‐mortem evidence of frequent steatosis in patients .…”

Section: Introductionmentioning

confidence: 99%

Frequent hepatic steatosis in amyotrophic lateral sclerosis: Implication for systemic involvement

Nodera

Takamatsu

Muguruma

et al. 2014

Neurology & Clinical Neurosc

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Background Abnormal energy metabolism has been reported in amyotrophic lateral sclerosis (ALS) that broadens the concept of ALS as a systemic disease. Dyslipidemia is likely to reflect the clinical outcome in ALS. Aim To study whether evidence of dysmetabolism can be detected non‐invasively by imaging study, such as liver sonography. Methods Abdominal sonography, lipid profiles and liver enzymes were obtained in three groups of individuals: (i) the patients with ALS; (ii) other neurodegenerative diseases; and (iii) asymptomatic dyslipidemic persons. The sonographic steatosis grade was determined by a blinded technician. Statistical tests including one‐way anova with post‐hoc test, multiple linear regression were carried out. Results The lipid profiles and liver enzymes were similar between the ALS and dyslipidemic groups. The disease control group had lower low‐density lipoprotein, low‐density lipoprotein‐to‐high‐density lipoprotein ratio and triglyceride than other groups. Hepatic steatosis was present in 76% of ALS patients, 19% of the disease control and 38% of the dyslipidemic group (P < 0.001 vs ALS). Multivariate analysis showed that only the patient group was correlated to the sonographic score. Conclusion The present study showed that hepatic steatosis is frequent and a unique phenomenon in ALS among neurodegenerative diseases. Hepatic steatosis might be a sensitive marker for dysmetabolism in ALS.

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A plural role for lipids in motor neuron diseases: energy, signaling and structure

Cited by 106 publications

References 127 publications

Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid

Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid

Combined Metabolomics and Transcriptomics Approaches to Assess the IL-6 Blockade as a Therapeutic of ALS: Deleterious Alteration of Lipid Metabolism

Frequent hepatic steatosis in amyotrophic lateral sclerosis: Implication for systemic involvement

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