Ataxin-2 (Atxn2)-Knock-Out Mice Show Branched Chain Amino Acids and Fatty Acids Pathway Alterations

Meierhofer, David; Halbach, Melanie Vanessa; Sen, Nesli Ece; Gispert, Suzana; Auburger, Georg

doi:10.1074/mcp.m115.056770

Cited by 89 publications

(67 citation statements)

References 79 publications

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“…Several lines of evidence implicate ataxin-2 in growth receptor regulation and RNA metabolism [25-28]. Recent expression profiling efforts in Atxn2 -knockoout mouse tissues demonstrated a selective downregulation of mitochondrial matrix components global proteome profiles and a preferential downregulation of calcium homeostasis factors together with an upregulation of mRNA translation factors in global transcriptomics [29-31]. The structure of ataxin-2 contains a PAM2 motif which mediates association with the poly(A)-binding protein PABP [12, 13, 32], thought to promote ataxin-2 association with polyribosomes [33].…”

Section: Introductionmentioning

confidence: 99%

Mammalian ataxin-2 modulates translation control at the pre-initiation complex via PI3K/mTOR and is induced by starvation

Lastres‐Becker

Nonis

Eich

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Ataxin-2 is a cytoplasmic protein, product of the ATXN2 gene, whose deficiency leads to obesity, while its gain-of-function leads to neural atrophy. Ataxin-2 affects RNA homeostasis, but its effects are unclear. Here, immunofluorescence analysis suggested that ataxin-2 associates with 48S pre-initiation components at stress granules in neurons and mouse embryonic fibroblast, but is not essential for stress granule formation. Coimmunoprecipitation analysis showed associations of ataxin-2 with initiation factors, which were concentrated at monosome fractions of polysome gradients like ataxin-2, unlike its known interactor PABP. Mouse embryonic fibroblasts lacking ataxin-2 showed increased phosphorylation of translation modulators 4E-BP1 and ribosomal protein S6 through the PI3K/mTOR pathways. Indeed, human neuroblastoma cells after trophic deprivation showed a strong induction of ATXN2 transcript via mTOR inhibition. Our results support the notion that ataxin-2 is a nutritional stress-inducible modulator of mRNA translation at the pre-initiation complex.

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Section: Introductionmentioning

confidence: 99%

Mammalian ataxin-2 modulates translation control at the pre-initiation complex via PI3K/mTOR and is induced by starvation

Lastres‐Becker

Nonis

Eich

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Mice lacking Atxn2 are viable but show adult-onset obesity and reduced insulin receptor expression (17,18). A recent study shows that Atxn2 modulates nutrition and metabolism by regulating the pathways for the metabolism of branched-chain and other amino acids, metabolism of fatty acids, and the citric acid cycle (19). Finally, the human locus containing SH2B3 and ATXN2 is associated with type 1 diabetes (20).…”

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confidence: 99%

Cell size and fat content of dietary-restricted Caenorhabditis elegans are regulated by ATX-2, an mTOR repressor

Bar

Charar

Dorfman

et al. 2016

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

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Dietary restriction (DR) is a metabolic intervention that extends the lifespan of multiple species, including yeast, flies, nematodes, rodents, and, arguably, rhesus monkeys and humans. Hallmarks of lifelong DR are reductions in body size, fecundity, and fat accumulation, as well as slower development. We have identified atx-2, the Caenorhabditis elegans homolog of the human ATXN2L and ATXN2 genes, as the regulator of these multiple DR phenotypes. Down-regulation of atx-2 increases the body size, cell size, and fat content of dietary-restricted animals and speeds animal development, whereas overexpression of atx-2 is sufficient to reduce the body size and brood size of wild-type animals. atx-2 regulates the mechanistic target of rapamycin (mTOR) pathway, downstream of AMP-activated protein kinase (AMPK) and upstream of ribosomal protein S6 kinase and mTOR complex 1 (TORC1), by its direct association with Rab GDP dissociation inhibitor β, which likely regulates RHEB shuttling between GDP-bound and GTP-bound forms. Taken together, this work identifies a previously unknown mechanism regulating multiple aspects of DR, as well as unknown regulators of the mTOR pathway. They also extend our understanding of diet-dependent growth retardation, and offers a potential mechanism to treat obesity.Caenorhabditis elegans | metabolism | mTOR pathway | TORC1 D ietary restriction (DR), limiting food consumption below ad libitum to levels that do not cause malnutrition, is a highly conserved metabolic intervention. Different DR regimes extend the lifespan of most tested animal species (1). Moreover, DR regimens have been found to reduce the risk of diabetes in monkeys and to positively change metabolic health biomarkers in humans (2). Lifelong DR causes reduced body size, lower fat levels, and a smaller brood size (3-6). Although the pathways by which DR extends lifespan have been thoroughly investigated, less is known about the causes of reduced body size and fat content.Multiple DR regimens have been developed for Caenorhabditis elegans (7). Surprisingly, the different DR regimens vary in the genes essential for lifespan extension (7). For example, DR can be achieved by diluting the bacteria in a liquid medium. This intervention, which extends the lifespan and decreases animal size, is partially dependent on both daf-16, a key transcription factor of the insulin-like signaling pathway, and aak-2, the catalytic subunit of AMP-activated protein kinase (AMPK) (7,8). In a different DR model, a mutation in the eat-2 gene decreases the rate of pharyngeal contractions, limiting the animals' feeding rate. Unlike bacterial dilution, this model was shown to be independent of both daf-16 and aak-2, at least with respect to lifespan (7).The mechanistic target of rapamycin (mTOR) pathway is a key regulator of multiple processes, including transcription and translation, protein and lipid synthesis, cell growth and size, and cellular metabolism (9). It contains two main protein complexes, mTOR complex 1 (TORC1) and complex 2 (TORC2) (10). TOR...

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“…A recently published study documented that ATXN2 regulates numerous nutrient enzymes in the mitochondrial matrix as well as key factors that may respond to altered Ca 2 + storage in mitochondria, ATXN2 mutations lead to a profound mitochondrial dysfunction [45]. Mouse studies showed the knock-out of ATXN2 to lead to obesity, insulin resistance, and dyslipidemia [46]. …”

Section: Discussionmentioning

confidence: 99%

Novel common variants associated with body mass index and coronary artery disease detected using a pleiotropic cFDR method

Zhang

Zhou

et al. 2017

Journal of Molecular and Cellular Cardiology

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Genome-wide association studies (GWAS) have been successfully applied in identifying single nucleotide polymorphisms (SNPs) associated with body mass index (BMI) and coronary heart disease (CAD). However, the SNPs to date can only explain a small percentage of the genetic variances of traits. Here, we applied a genetic pleiotropic conditional false discovery rate (cFDR) method that combines summary statistic p values from different multi-center GWAS datasets, to detect common genetic variants associated with these two traits. The enrichment of SNPs associated with BMI and CAD was assessed by conditional Q-Q plots and the common variants were identified by the cFDR method. By applying the cFDR level of 0.05, 7 variants were identified to be associated with CAD (2 variants being novel), 34 variants associated with BMI (11 variants being novel), and 3 variants associated with both BMI and CAD (2 variants being novel). The SNP rs653178 (ATXN2) is noteworthy as this variant was replicated in an independent analysis. SNP rs12411886 (CNNM2) and rs794356 (HIP1) were of note as the annotated genes may be associated with processes that are functionally important in lipid metabolism. In conclusion, the cFDR method identified novel variants associated with BMI and/or CAD by effectively incorporating different GWAS datasets.

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Ataxin-2 (Atxn2)-Knock-Out Mice Show Branched Chain Amino Acids and Fatty Acids Pathway Alterations

Cited by 89 publications

References 79 publications

Mammalian ataxin-2 modulates translation control at the pre-initiation complex via PI3K/mTOR and is induced by starvation

Mammalian ataxin-2 modulates translation control at the pre-initiation complex via PI3K/mTOR and is induced by starvation

Cell size and fat content of dietary-restricted Caenorhabditis elegans are regulated by ATX-2, an mTOR repressor

Novel common variants associated with body mass index and coronary artery disease detected using a pleiotropic cFDR method

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