scholarly journals Disordered Expression of shaggy, the Drosophila Gene Encoding a Serine-Threonine Protein Kinase GSK3, Affects the Lifespan in a Transcript-, Stage-, and Tissue-Specific Manner

2019 ◽  
Vol 20 (9) ◽  
pp. 2200 ◽  
Author(s):  
Mikhail V. Trostnikov ◽  
Natalia V. Roshina ◽  
Stepan V. Boldyrev ◽  
Ekaterina R. Veselkina ◽  
Andrey A. Zhuikov ◽  
...  
Keyword(s):  
Nervous System ◽  
Protein Kinase ◽  
Glycogen Synthase ◽  
Accelerated Aging ◽  
Premature Aging ◽  
Synaptic Activity ◽  
Protein Isoforms ◽  
Gene Encoding ◽  
Tissue Specific ◽  
Regulatory Pathways

GSK3 (glycogen synthase kinase 3) is a conserved protein kinase governing numerous regulatory pathways. In Drosophila melanogaster, GSK3 is encoded by shaggy (sgg), which forms 17 annotated transcripts corresponding to 10 protein isoforms. Our goal was to demonstrate how differential sgg transcription affects lifespan, which GSK3 isoforms are important for the nervous system, and which changes in the nervous system accompany accelerated aging. Overexpression of three sgg transcripts affected the lifespan in a stage- and tissue-specific way: sgg-RA and sgg-RO affected the lifespan only when overexpressed in muscles and in embryos, respectively; the essential sgg-RB transcript affected lifespan when overexpressed in all tissues tested. In the nervous system, only sgg-RB overexpression affected lifespan, causing accelerated aging in a neuron-specific way, with the strongest effects in dopaminergic neurons and the weakest effects in GABAergic neurons. Pan-neuronal sgg-RB overexpression violated the properties of the nervous system, including the integrity of neuron bodies; the number, distribution, and structure of mitochondria; cytoskeletal characteristics; and synaptic activity. Such changes observed in young individuals indicated premature aging of their nervous system, which paralleled a decline in survival. Our findings demonstrated the key role of GSK3 in ensuring the link between the pathology of neurons and lifespan.

scholarly journals Antagonistic Controls of Autophagy and Glycogen Accumulation by Snf1p, the Yeast Homolog of AMP-Activated Protein Kinase, and the Cyclin-Dependent Kinase Pho85p

2001 ◽  
Vol 21 (17) ◽  
pp. 5742-5752 ◽  
Author(s):  
Zhong Wang ◽  
Wayne A. Wilson ◽  
Marie A. Fujino ◽  
Peter J. Roach
Keyword(s):  
Protein Kinase ◽  
Stationary Phase ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Glycogen Storage ◽  
Wild Type ◽  
Gene Encoding ◽  
Glycogen Accumulation ◽  
Yeast Homolog ◽  
Glycogen Stores

ABSTRACT In the yeast Saccharomyces cerevisiae, glycogen is accumulated as a carbohydrate reserve when cells are deprived of nutrients. Yeast mutated in SNF1, a gene encoding a protein kinase required for glucose derepression, has diminished glycogen accumulation and concomitant inactivation of glycogen synthase. Restoration of synthesis in an snf1 strain results only in transient glycogen accumulation, implying the existence of otherSNF1-dependent controls of glycogen storage. A genetic screen revealed that two genes involved in autophagy, APG1and APG13, may be regulated by SNF1. Increased autophagic activity was observed in wild-type cells entering the stationary phase, but this induction was impaired in ansnf1 strain. Mutants defective for autophagy were able to synthesize glycogen upon approaching the stationary phase, but were unable to maintain their glycogen stores, because subsequent synthesis was impaired and degradation by phosphorylase, Gph1p, was enhanced. Thus, deletion of GPH1 partially reversed the loss of glycogen accumulation in autophagy mutants. Loss of the vacuolar glucosidase, SGA1, also protected glycogen stores, but only very late in the stationary phase. Gph1p and Sga1p may therefore degrade physically distinct pools of glycogen. Pho85p is a cyclin-dependent protein kinase that antagonizes SNF1control of glycogen synthesis. Induction of autophagy inpho85 mutants entering the stationary phase was exaggerated compared to the level in wild-type cells, but was blocked in apg1 pho85 mutants. We propose that Snf1p and Pho85p are, respectively, positive and negative regulators of autophagy, probably via Apg1 and/or Apg13. Defective glycogen storage in snf1cells can be attributed to both defective synthesis upon entry into stationary phase and impaired maintenance of glycogen levels caused by the lack of autophagy.

Seasonal, tissue-specific regulation of Akt/protein kinase B and glycogen synthase in hibernators

2004 ◽  
Vol 286 (3) ◽  
pp. R498-R504 ◽  
Author(s):  
Kyle L. Hoehn ◽  
Susan F. Hudachek ◽  
Scott A. Summers ◽  
Gregory L. Florant
Keyword(s):  
Protein Kinase ◽  
Body Mass ◽  
Large Scale ◽  
Glycogen Synthase ◽  
Protein Kinase B ◽  
Glycogen Synthesis ◽  
Mass Gain ◽  
Tissue Specific ◽  
Protein Levels ◽  
Specific Regulation

Yellow-bellied marmots ( Marmota flaviventris) exhibit a circannual cycle of hyperphagia and nutrient storage in the summer followed by hibernation in the winter. This annual cycle of body mass gain and loss is primarily due to large-scale accumulation of lipid in the summer, which is then mobilized and oxidized for energy during winter. The rapid and predictable change in body mass makes these animals ideal for studies investigating the molecular basis for body weight regulation. In the study described herein, we monitored seasonal changes in the protein levels and activity of a central regulator of anabolic metabolism, the serine-threonine kinase Akt-protein kinase B (Akt/PKB), during the months accompanying maximal weight gain and entry into hibernation (June-November). Interestingly, under fasting conditions, Akt/PKB demonstrated a tissue-specific seasonal activation. Specifically, although Akt/PKB levels did not change, the activity of Akt/PKB (isoforms 1/α and 2/β) in white adipose tissue (WAT) increased significantly in July. Moreover, glycogen synthase, which lies downstream of Akt/PKB on a linear pathway linking the enzyme to the stimulation of glycogen synthesis, demonstrated a similar pattern of seasonal activation. By contrast, Akt/PKB activity in skeletal muscle peaked much later (i.e., September). These data suggest the existence of a novel, tissue-specific mechanism regulating Akt/PKB activation during periods of marked anabolism.

scholarly journals Characterisation of protein isoforms encoded by the Drosophila Glycogen Synthase Kinase 3 gene shaggy

2019 ◽  
Author(s):  
Dagmara Korona ◽  
Daniel J. H. Nightingale ◽  
Bertrand Fabre ◽  
Michael Nelson ◽  
Bettina Fischer ◽  
...  
Keyword(s):  
Nervous System ◽  
Genome Engineering ◽  
Glycogen Synthase ◽  
Affinity Purification ◽  
Protein Isoforms ◽  
Phenotypic Analysis ◽  
Specific Expression ◽  
Adult Lifespan ◽  
Gsk 3Β ◽  
Developmental Signalling

AbstractThe Drosophila shaggy gene (sgg, GSK-3) encodes multiple protein isoforms with serine/threonine kinase activity and is a key player in diverse developmental signalling pathways. Currently it is unclear whether different Sgg proteoforms are similarly involved in signalling or if different proteoforms have distinct functions. We used CRISPR/Cas9 genome engineering to tag eight different Sgg proteoform classes and determined their localization during embryonic development. We performed proteomic analysis of the two major proteoform classes and generated mutant lines for both of these for transcriptomic and phenotypic analysis. We uncovered distinct tissue-specific localization patterns for all of the tagged proteoforms we examined, most of which have not previously been characterised directly at the protein level, including one proteoform initiating with a non-standard codon. Collectively this suggests complex developmentally regulated splicing of the sgg primary transcript. Further, affinity purification followed by mass spectrometric analyses indicate a different repertoire of interacting proteins for the two major proteoform classes we examined, one with ubiquitous expression (Sgg-PB) and one with nervous system specific expression (Sgg-PA). Specific mutation of these proteoforms shows that Sgg-PB performs the well characterised maternal and zygotic segmentations functions of the sgg locus, while Sgg-PA mutants show adult lifespan and locomotor defects consistent with its nervous system localisation. Our findings provide new insights into the role of GSK-3 proteoforms and intriguing links with the GSK-3α and GSK-3β encoded by independent vertebrate genes. Our analysis suggests that different protein isoforms generated by alternative splicing perform distinct functions.

scholarly journals NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Evandro F. Fang ◽  
Yujun Hou ◽  
Sofie Lautrup ◽  
Martin Borch Jensen ◽  
Beimeng Yang ◽  
...  
Keyword(s):  
Werner Syndrome ◽  
Accelerated Aging ◽  
Dna Helicase ◽  
Premature Aging ◽  
Metabolic Dysfunction ◽  
Gene Encoding ◽  
Metabolic Phenotypes ◽  
Cell Dysfunction ◽  
Underlying Mechanisms ◽  
Invertebrate Models

AbstractMetabolic dysfunction is a primary feature of Werner syndrome (WS), a human premature aging disease caused by mutations in the gene encoding the Werner (WRN) DNA helicase. WS patients exhibit severe metabolic phenotypes, but the underlying mechanisms are not understood, and whether the metabolic deficit can be targeted for therapeutic intervention has not been determined. Here we report impaired mitophagy and depletion of NAD+, a fundamental ubiquitous molecule, in WS patient samples and WS invertebrate models. WRN regulates transcription of a key NAD+ biosynthetic enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1). NAD+ repletion restores NAD+ metabolic profiles and improves mitochondrial quality through DCT-1 and ULK-1-dependent mitophagy. At the organismal level, NAD+ repletion remarkably extends lifespan and delays accelerated aging, including stem cell dysfunction, in Caenorhabditis elegans and Drosophila melanogaster models of WS. Our findings suggest that accelerated aging in WS is mediated by impaired mitochondrial function and mitophagy, and that bolstering cellular NAD+ levels counteracts WS phenotypes.

Sign in / Sign up

Export Citation Format

Share Document