Fang EF et al. (2019) Nat Commun "NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome."

Rusten TE, Hou Y, Yokote K, SenGupta T, Lee JH, Filippelli D, Morevati M, Fang EF, Yang B, Mangerich A, Aman Y, Kassahun H, Jasper H, Okur MN, Croteau DL, Maezawa Y, Tao J, Caponio D, Lautrup S, Lyssiotis CA, Kato H, Bohr VA, Lee HJ, Demarest TG, Jensen MB, Nilsen H, Mattson MP, Khezri R, Figueroa D

[Nat Commun, 2019]

Metabolic 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.

Sawada D et al. (2023) Aging (Albany NY) "Senescence-associated inflammation and inhibition of adipogenesis in subcutaneous fat in Werner syndrome."

Yamaguchi A, Ide K, Kubota Y, Fujii K, Takasaki A, Nakamura R, Hayashi A, Takayama N, Kitamoto T, Ogata H, Takada-Watanabe A, Ohno T, Iwama A, Kinoshita D, Koshizaka M, Yokote K, Funayama S, Teramoto N, Kaneko H, Eto K, Aono K, Mitsukawa N, Ide S, Endo Y, Sawada D, Shiohama T, Ouchi Y, Maeda Y, Maezawa Y, Takatani T, Kato H, Igarashi K, Minamizuka T, Hamada H, Shoji M

[Aging (Albany NY), 2023]

Werner syndrome (WS) is a hereditary premature aging disorder characterized by visceral fat accumulation and subcutaneous lipoatrophy, resulting in severe insulin resistance. However, its underlying mechanism remains unclear. In this study, we show that senescence-associated inflammation and suppressed adipogenesis play a role in subcutaneous adipose tissue reduction and dysfunction in WS. Clinical data from four Japanese patients with WS revealed significant associations between the decrease of areas of subcutaneous fat and increased insulin resistance measured by the glucose clamp. Adipose-derived stem cells from the stromal vascular fraction derived from WS subcutaneous adipose tissues (WSVF) showed early replicative senescence and a significant increase in the expression of senescence-associated secretory phenotype (SASP) markers. Additionally, adipogenesis and insulin signaling were suppressed in WSVF, and the expression of adipogenesis suppressor genes and SASP-related genes was increased. Rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), alleviated premature cellular senescence, rescued the decrease in insulin signaling, and extended the lifespan of WS model of <i>C. elegans</i>. To the best of our knowledge, this study is the first to reveal the critical role of cellular senescence in subcutaneous lipoatrophy and severe insulin resistance in WS, highlighting the therapeutic potential of rapamycin for this disease.

Oshima H et al. (2007) Phys Rev E Stat Nonlin Soft Matter Phys "Storage capacity and retrieval time of small-world neural networks."

Odagaki T, Oshima H

[Phys Rev E Stat Nonlin Soft Matter Phys, 2007]

To understand the influence of structure on the function of neural networks, we study the storage capacity and the retrieval time of Hopfield-type neural networks for four network structures: regular, small world, random networks generated by the Watts-Strogatz (WS) model, and the same network as the neural network of the nematode Caenorhabditis elegans. Using computer simulations, we find that (1) as the randomness of network is increased, its storage capacity is enhanced; (2) the retrieval time of WS networks does not depend on the network structure, but the retrieval time of C. elegans''s neural network is longer than that of WS networks; (3) the storage capacity of the C. elegans network is smaller than that of networks generated by the WS model, though the neural network of C. elegans is considered to be a small-world network.

Dallaire A et al. (2012) Aging (Albany NY) "Down regulation of miR-124 in both Werner syndrome DNA helicase mutant mice and mutant Caenorhabditis elegans wrn-1 reveals the importance of this microRNA in accelerated aging."

Mitchell SJ, Dallaire A, Lebel M, Simard MJ, Paquel ER, De Cabo R, Garand C

[Aging (Albany NY), 2012]

Small non-coding microRNAs are believed to be involved in the mechanism of aging but nothing is known on the impact of microRNAs in the progeroid disorder Werner syndrome (WS). WS is a premature aging disorder caused by mutations in a RecQ-like DNA helicase. Mice lacking the helicase domain of the WRN ortholog exhibit many phenotypic features of WS, including a pro-oxidant status and a shorter mean life span.Caenorhabditis elegans (C. elegans) with a nonfunctional wrn-1 DNA helicase also exhibit a shorter life span. Thus, both models are relevant to study the expression of microRNAs involved in WS. In this study, we show that miR-124 expression is lost in the liver of Wrn helicase mutant mice. Interestingly, the expression of this conserved miR-124 in whole wrn-1 mutant worms is also significantly reduced. The loss of mir-124 in C. elegans increases reactive oxygen species formation and accumulation of the aging marker lipofuscin, reduces whole body ATP levels and results in a reduction in life span. Finally, supplementation of vitamin C normalizes the median life span of wrn-1 and mir-124 mutant worms. These results suggest that biological pathways involving WRN and miR-124 are conserved in the aging process across different species.

Gui JF et al. (1994) Nature "A serine kinase regulates intracellular localization of splicing factors in the cell cycle [see comments]"

Lane WS, Fu XD, Gui JF

[Nature, 1994]

Small nuclear ribonucleoprotein particles (snRNPs) and non-snRNP splicing factors containing a serine/arginine-rich domain (SR proteins) concentrate in 'speckles' in the nucleus of interphase cells. It is believed that nuclear speckles act as storage sites for splicing factors while splicing occurs on nascent transcripts. Splicing factors redistribute in response to transcription inhibition or viral infection, and nuclear speckles break down and reform as cells progress through mitosis. We have now identified and cloned a kinase, SRPK1, which is regulated by the cell cycle and is specific for SR proteins; this kinase is related to a Caenorhabditis elegans kinase and to the fission yeast kinase Dsk1 (ref. 7). SRPK1 specifically induces the disassembly of nuclear speckles, and a high level of SRPK1 inhibits splicing in vitro. Our results indicate that SRPK1 may have a central role in the regulatory network for splicing, controlling the intranuclear distribution of splicing factors in interphase cells, and the reorganization of nuclear speckles during mitosis.

Liu X et al. (2022) Chemosphere "Ecotoxicity induced by total, water soluble and insoluble components of atmospheric fine particulate matter exposure in Caenorhabditis elegans."

Lu Z, Yan Z, Liu X, Cao M, Ge P, Chen M, Wang J, Chen W

[Chemosphere, 2022]

Although PM_2.5 could cause toxicity in environmental organisms, the toxicity difference of PM_2.5 under different solubilities is still poorly understood. To acquire a better knowledge of the ecotoxicity of PM_2.5 under different solubilities, the model animal Caenorhabditis elegans (C. elegans) was exposed to Total-PM_2.5, water insoluble components of PM_2.5 (WIS-PM_2.5) and water soluble components of PM_2.5 (WS-PM_2.5). The physiological (growth, locomotion behavior, and reproduction), biochemical (germline apoptosis, and reactive oxygen species (ROS) production) indices, and the related gene expression were examined. According to the findings, acute exposure to these three components caused adverse physiological effects on growth and locomotion behavior, and significantly induced germline apoptosis or ROS production. In contrast, prolonged exposure showed stronger adverse effects than acute exposure. Additionally, the results of multiple toxicological endpoints showed that the toxicity effects of WIS-PM_2.5 are more intense than WS-PM_2.5, which means that insoluble components contributed more to the toxicity of PM_2.5. Prolonged exposure to 1000&#x202f;mg/L WS-PM_2.5, WIS-PM_2.5, and Total-PM_2.5 dramatically altered the expression of stress-related genes, which further indicated that apoptosis, DNA damage and oxidative stress play a crucial part in toxicity induced by PM_2.5.

Fuhrman JA et al. (1992) Proc Natl Acad Sci U S A "Transmission-blocking antibodies recognize microfilarial chitinase in brugian lymphatic filariasis."

Lane WS, Fuhrman JA, Piessens WF, Smith RF, Perler FB

[Proc Natl Acad Sci U S A, 1992]

Brugia malayi is a parasitic nematode that causes lymphatic filariasis in humans. The monoclonal antibody MF1, which mediates clearance of peripheral microfilaremia in a gerbil infection model, recognizes two stage-specific proteins, p70 and p75, in B. malayi microfilariae. cDNA coding for the MF1 antigen was sequenced, and the predicted protein sequence shows significant similarities to chitinases from bacteria and yeast. When microfilarial extracts and purified preparations of the MF1 antigen were tested for chitinase activity, strong bands of chitin-degrading activity comigrated in SDS/PAGE with p70 and p75 and showed a reduction-dependent mobility shift characteristic of the MF1 antigen. Thus, the MF1 antigen is microfilarial chitinase, which may function to degrade chitin-containing structures in the microfilaria or in its mosquito vector during parasite development and transmission.

Sano H et al. (2003) J Biol Chem "Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation."

Garner CW, Kane S, Sano E, Sano H, Asara JM, Lienhard GE, Miinea CP, Lane WS

[J Biol Chem, 2003]

Insulin stimulates the rapid translocation of intracellular glucose transporters of the GLUT4 isotype to the plasma membrane in fat and muscle cells. The connections between known insulin signaling pathways and the protein machinery of this membrane-trafficking process have not been fully defined. Recently, we identified a 160-kDa protein in adipocytes, designated AS160, that is phosphorylated by the insulin-activated kinase Akt. This protein contains a GTPase-activating domain (GAP) for Rabs, which are small G proteins required for membrane trafficking. In the present study we have identified six sites of in vivo phosphorylation on AS160. These sites lie in the motif characteristic of Akt phosphorylation, and insulin treatment increased phosphorylation at five of the sites. Expression of AS160 with two or more of these sites mutated to alanine markedly inhibited insulin-stimulated GLUT4 translocation in 3T3-L1 adipocytes. Moreover, this inhibition did not occur when the GAP function in the phosphorylation site mutant was inactivated by a point mutation. These findings strongly indicate that insulin-stimulated phosphorylation of AS160 is required for GLUT4 translocation and that this phosphorylation signals translocation through inactivation of the Rab GAP function.

Li S et al. (2022) Front Neurosci "Energy efficiency and coding of neural network."

Yan C, Liu Y, Li S

[Front Neurosci, 2022]

Based on the Hodgkin-Huxley model, this study explored the energy efficiency of BA network, ER network, WS network, and Caenorhabditis elegans neural network, and explained the development of neural network structure in the brain from the perspective of energy efficiency using energy coding theory. The numerical simulation results showed that the BA network had higher energy efficiency, which was closer to that of the C. elegans neural network, indicating that the neural network in the brain had scale-free property because of satisfying high energy efficiency. In addition, the relationship between the energy consumption of neural networks and synchronization was established by applying energy coding. The stronger the neural network synchronization was, the less energy the network consumed.

Chinnaiyan AM et al. (1997) Science "Interaction of CED-4 with CED-3 and CED-9: a molecular framework for cell death."

Chinnaiyan AM, O'Rourke K, Lane BR, Dixit VM

[Science, 1997]

Previous genetic studies of the nematode Caenorhabditis elegans identified three important components of the cell death machinery. CED-3 and CED-4 function to kill cells, whereas CED-9 protects cells from death. Here CED-9 and its mammalian homolog Bcl-xL (a member of the Bcl-2 family of cell death regulators) were both found to interact with and inhibit the function of CED-4. In addition, analysis revealed that CED-4 can simultaneously interact with CED-3 and its mammalian counterparts interleukin-1beta-converting enzyme (ICE) and FLICE. Thus, CED-4 plays a central role in the cell death pathway, biochemically linking CED-9 and the Bcl-2 family to CED-3 and the ICE family of pro-apoptotic cysteine proteases.AD - University of Michigan Medical School, Department of Pathology, Ann Arbor, MI 48109, USA.FAU - Chinnaiyan, A MAU - Chinnaiyan AMFAU - O'Rourke, KAU - O'Rourke KFAU - Lane, B RAU - Lane BRFAU - Dixit, V MAU - Dixit VMLA - engID - 7863/PHSPT - Journal ArticleCY - UNITED STATESTA - ScienceJID - 0404511RN - 0 (Calcium-Binding Proteins)RN - 0 (Ced-4 protein)RN - 0 (Ced-9 protein)RN - 0 (Helminth Proteins)RN - 0 (Proto-Oncogene Proteins)RN - 0 (bcl-x protein)RN - EC 3.4.22 (Cysteine Endopeptidases)RN - EC 3.4.22.- (Ced-3 protein)RN - EC 3.4.22.- (caspase 8)RN - EC 3.4.22.36 (Caspase 1)SB - IM