Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of mice overexpressing spermidine/spermine N1-acetyltransferase (SSAT)

ABSTRACT: Type 2 diabetes is a complex disorder due to defects in insulin secretion and insulin action. Therefore, we investigated mice overexpressing spermidine/spermine N1-acetyltransferase (SSAT) have reduced amount of white adipose tissue, high basal metabolic rate, improved glucose tolerance, high insulin sensitivity, and a low accumulation of triglycerides in liver and skeletal muscle. Our aim was to elucidate the molecular mechanisms leading to the phenotype of SSAT mice.

ORGANISM(S): Mus musculus

SUBMITTER: Joanna Skommer

PROVIDER: E-MEXP-165 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Enhanced polyamine catabolism alters homeostatic control of white adipose tissue mass, energy expenditure, and glucose metabolism.

Pirinen Eija E Kuulasmaa Teemu T Pietilä Marko M Heikkinen Sami S Tusa Maija M Itkonen Paula P Boman Susanna S Skommer Joanna J Virkamäki Antti A Hohtola Esa E Kettunen Mikko M Fatrai Szabolcs S Kansanen Emilia E Koota Suvi S Niiranen Kirsi K Parkkinen Jyrki J Levonen Anna-Liisa AL Ylä-Herttuala Seppo S Hiltunen J Kalervo JK Alhonen Leena L Smith Ulf U Jänne Juhani J Laakso Markku M

Molecular and cellular biology 20070507 13

Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) is an attractive candidate gene for type 2 diabetes, as genes of the oxidative phosphorylation (OXPHOS) pathway are coordinatively downregulated by reduced expression of PGC-1 alpha in skeletal muscle and adipose tissue of patients with type 2 diabetes. Here we demonstrate that transgenic mice with activated polyamine catabolism due to overexpression of spermidine/spermine N(1)-acetyltransferase (SSAT) had reduced ...[more]

PMID: 17485446

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Project description:BACKGROUND:Tau stabilizes microtubules; however, in Alzheimer's disease (AD) and tauopathies, tau becomes hyperphosphorylated, aggregates, and results in neuronal death. Our group recently uncovered a unique interaction between polyamine metabolism and tau fate. Polyamines exert an array of physiological effects that support neuronal function and cognitive processing. Specific stimuli can elicit a polyamine stress response (PSR), resulting in altered central polyamine homeostasis. Evidence suggests that elevations in polyamines following a short-term stressor are beneficial; however, persistent stress and subsequent PSR activation may lead to maladaptive polyamine dysregulation, which is observed in AD, and may contribute to neuropathology and disease progression. METHODS:Male and female mice harboring tau P301L mutation (rTg4510) were examined for a tau-induced central polyamine stress response (tau-PSR). The direct effect of tau-PSR byproducts on tau fibrillization and oligomerization were measured using a thioflavin T assay and a N2a split superfolder GFP-Tau (N2a-ssGT) cell line, respectively. To therapeutically target the tau-PSR, we bilaterally injected caspase 3-cleaved tau truncated at aspartate 421 (AAV9 Tau ΔD421) into the hippocampus and cortex of spermidine/spermine-N1-acetyltransferase (SSAT), a key regulator of the tau-PSR, knock out (SSAT-/-), and wild type littermates, and the effects on tau neuropathology, polyamine dysregulation, and behavior were measured. Lastly, cellular models were employed to further examine how SSAT repression impacted tau biology. RESULTS:Tau induced a unique tau-PSR signature in rTg4510 mice, notably in the accumulation of acetylated spermidine. In vitro, higher-order polyamines prevented tau fibrillization but acetylated spermidine failed to mimic this effect and even promoted fibrillization and oligomerization. AAV9 Tau ΔD421 also elicited a unique tau-PSR in vivo, and targeted disruption of SSAT prevented the accumulation of acetylated polyamines and impacted several tau phospho-epitopes. Interestingly, SSAT knockout mice presented with altered behavior in the rotarod task, the elevated plus maze, and marble burying task, thus highlighting the impact of polyamine homeostasis within the brain. CONCLUSION:These data represent a novel paradigm linking tau pathology and polyamine dysfunction and that targeting specific arms within the polyamine pathway may serve as new targets to mitigate certain components of the tau phenotype.

Dataset Information

Transcription profiling of mice overexpressing spermidine/spermine N1-acetyltransferase (SSAT)

Publications

Enhanced polyamine catabolism alters homeostatic control of white adipose tissue mass, energy expenditure, and glucose metabolism.

Similar Datasets

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