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Genetic ablation of IP3 receptor 2 increases cytokines and decreases survival of SOD1G93A mice.

ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disease characterized by the selective death of motor neurons. Disease pathophysiology is complex and not yet fully understood. Higher gene expression of the inositol 1,4,5-trisphosphate receptor 2 gene (ITPR2), encoding the IP₃ receptor 2 (IP₃R2), was detected in sporadic ALS patients. Here, we demonstrate that IP₃R2 gene expression was also increased in spinal cords of ALS mice. Moreover, an increase of IP₃R2 expression was observed in other models of chronic and acute neurodegeneration. Upregulation of IP₃R2 gene expression could be induced by lipopolysaccharide (LPS) in murine astrocytes, murine macrophages and human fibroblasts indicating that it may be a compensatory response to inflammation. Preventing this response by genetic deletion of ITPR2 from SOD1^G93A mice had a dose-dependent effect on disease duration, resulting in a significantly shorter lifespan of these mice. In addition, the absence of IP₃R2 led to increased innate immunity, which may contribute to the decreased survival of the SOD1^G93A mice. Besides systemic inflammation, IP₃R2 knockout mice also had increased IFNγ, IL-6 and IL1α expression. Altogether, our data indicate that IP₃R2 protects against the negative effects of inflammation, suggesting that the increase in IP₃R2 expression in ALS patients is a protective response.

SUBMITTER: Staats KA

PROVIDER: S-EPMC5179944 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Genetic ablation of IP3 receptor 2 increases cytokines and decreases survival of SOD1G93A mice.

Staats Kim A KA Humblet-Baron Stephanie S Bento-Abreu Andre A Scheveneels Wendy W Nikolaou Alexandros A Deckers Kato K Lemmens Robin R Goris An A Van Ginderachter Jo A JA Van Damme Philip P Hisatsune Chihiro C Mikoshiba Katsuhiko K Liston Adrian A Robberecht Wim W Van Den Bosch Ludo L

Human molecular genetics 20160704 16

Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disease characterized by the selective death of motor neurons. Disease pathophysiology is complex and not yet fully understood. Higher gene expression of the inositol 1,4,5-trisphosphate receptor 2 gene (ITPR2), encoding the IP3 receptor 2 (IP3R2), was detected in sporadic ALS patients. Here, we demonstrate that IP3R2 gene expression was also increased in spinal cords of ALS mice. ...[more]

PMID: 27378687

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Project description:Spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders, caused or modified by an unstable CAG-repeat expansion in the SCA2 gene, which encodes a polyglutamine (polyQ) domain expansion in ataxin-2 (ATXN2). ATXN2 is an RNA-binding protein and interacts with the poly(A)-binding protein PABPC1, localizing to ribosomes at the rough endoplasmic reticulum. Under cell stress, ATXN2, PABPC1 and small ribosomal subunits are relocated to stress granules, where mRNAs are protected from translation and from degradation. It is unknown whether ATXN2 associates preferentially with specific mRNAs or how it modulates RNA processing. Here, we investigated the RNA profile of the liver and cerebellum from Atxn2 knockout (Atxn2 (-/-)) mice at two adult ages, employing oligonucleotide microarrays. Prominent increases were observed for Lsm12/Paip1 (>2-fold), translation modulators known as protein interactor/competitor of ATXN2 and for Plin3/Mttp (>1.3-fold), known as apolipoprotein modulators in agreement with the hepatosteatosis phenotype of the Atxn2 (-/-) mice. Consistent modest upregulations were also observed for many factors in the ribosome and the translation/secretion apparatus. Quantitative reverse transcriptase PCR in liver tissue validated >1.2-fold upregulations for the ribosomal biogenesis modulator Nop10, the ribosomal components Rps10, Rps18, Rpl14, Rpl18, Gnb2l1, the translation initiation factors Eif2s2, Eif3s6, Eif4b, Pabpc1 and the rER translocase factors Srp14, Ssr1, Sec61b. Quantitative immunoblots substantiated the increased abundance of NOP10, RPS3, RPS6, RPS10, RPS18, GNB2L1 in SDS protein fractions, and of PABPC1. In mouse embryonal fibroblasts, ATXN2 absence also enhanced phosphorylation of the ribosomal protein S6 during growth stimulation, while impairing the rate of overall protein synthesis rates, suggesting a block between the enhanced translation drive and the impaired execution. Thus, the physiological role of ATXN2 subtly modifies the abundance of cellular translation factors as well as global translation.

Project description:BackgroundAmyotrophic lateral sclerosis (ALS) is characterized by a gradual muscular paralysis resulting from progressive motoneurons death. ALS etiology remains unknown although it has been demonstrated to be a multifactorial disease involving several cellular partners. There is currently no effective treatment. Even if the effect of exercise is under investigation for many years, whether physical exercise is beneficial or harmful is still under debate.Methods and findingsWe investigated the effect of three different intensities of running exercises on the survival of SOD1(G93A) mice. At the early-symptomatic stage (P60), males were isolated and randomly assigned to 5 conditions: 2 sedentary groups ("sedentary" and "sedentary treadmill" placed on the inert treadmill), and 3 different training intensity groups (5 cm/s, 10 cm/s and 21 cm/s; 15 min/day, 5days/week). We first demonstrated that an appropriate "control" of the environment is of the utmost importance since comparison of the two sedentary groups evidenced an 11.6% increase in survival in the "sedentary treadmill" group. Moreover, we showed by immunohistochemistry that this increased lifespan is accompanied with motoneurons survival and increased glial reactivity in the spinal cord. In a second step, we showed that when compared with the proper control, all three running-based training did not modify lifespan of the animals, but result in motoneurons preservation and changes in glial cells activation.Conclusions/significanceWe demonstrate that increase in survival induced by a slight daily modification of the environment is associated with motoneurons preservation and strong glial modifications in the lumbar spinal cord of SOD1(G93A). Using the appropriate control, we then demonstrate that all running intensities have no effect on the survival of ALS mice but induce cellular modifications. Our results highlight the critical importance of the control of the environment in ALS studies and may explain discrepancy in the literature regarding the effect of exercise in ALS.

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Genetic ablation of IP3 receptor 2 increases cytokines and decreases survival of SOD1G93A mice.

Publications

Genetic ablation of IP3 receptor 2 increases cytokines and decreases survival of SOD1G93A mice.

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