scholarly journals Lipid droplets modulate proteostasis, SQST-1/SQSTM1 dynamics, and lifespan in C. elegans

2021 ◽  
Author(s):  
Anita Kumar ◽  
Joslyn Mills ◽  
Wesley Parker ◽  
Joshua Leitão ◽  
Celeste Ng ◽  
...  
Keyword(s):  
Translational Regulation ◽  
Lipid Droplets ◽  
Dependent Manner ◽  
Lipase Gene ◽  
Triacylglycerol Lipase ◽  
Selective Autophagy ◽  
C Elegans ◽  
Protein Ubiquitination ◽  
Model Of Alzheimer’S Disease ◽  
Age Related

Abstract The ability of organisms to live long depends largely on the maintenance of proteome stability via proteostatic mechanisms including translational regulation, protein chaperoning and degradation machineries. In several long-lived Caenorhabditis elegans strains, such as insulin/IGF-1 receptor daf-2 mutants, enhanced proteostatic mechanisms are accompanied by elevated intestinal lipid stores, but the role of lipid droplets in longevity has remained obscure. Here, while determining the regulatory network of the selective autophagy receptor SQST-1/SQSTM1, we unexpectedly uncovered a novel role for lipid droplets in proteostasis and longevity. Using an unbiased genomewide RNAi screening approach, we identified several SQST-1 modulators, including proteins found on lipid droplets and those prone to aggregate with age. SQST-1 accumulated on lipid droplets when autophagy was inhibited, suggesting that lipid droplets may serve a role in facilitating selective autophagy. Expansion of intestinal lipid droplets by silencing the conserved cytosolic triacylglycerol lipase gene atgl-1/ATGL enhanced autophagy, and extended lifespan in an HSF-1/HSF1-dependent and CDC-48/VCP-dependent manner. Silencing atgl-1 mitigated the age-related accumulation of SQST-1 and reduced overall ubiquitination of proteins. Reducing atgl-1 also improved proteostasis in a nematode model of Alzheimer’s disease. Subcellular analyses revealed that lipid droplets unexpectedly harbor more ubiquitinated proteins than the cytosol. Accordingly, low lipid droplet levels exacerbated the proteostatic collapse when autophagy or proteasome function was compromised. Altogether, our study uncovers a key role for lipid droplets in C. elegans as a proteostatic mediator that reduces protein ubiquitination, facilitates autophagy, and promotes longevity.

scholarly journals Lipid droplets modulate proteostasis, SQST-1/SQSTM1 dynamics, and lifespan in C. elegans

2021 ◽  
Author(s):  
Anita V. Kumar ◽  
Joslyn Mills ◽  
Wesley M. Parker ◽  
Joshua A. Leitão ◽  
Celeste Ng ◽  
...  
Keyword(s):  
Translational Regulation ◽  
Lipid Droplets ◽  
Dependent Manner ◽  
Lipase Gene ◽  
Triacylglycerol Lipase ◽  
Selective Autophagy ◽  
C Elegans ◽  
Protein Ubiquitination ◽  
Model Of Alzheimer’S Disease ◽  
Age Related

ABSTRACTThe ability of organisms to live long depends largely on the maintenance of proteome stability via proteostatic mechanisms including translational regulation, protein chaperoning and degradation machineries. In several long-lived Caenorhabditis elegans strains, such as insulin/IGF-1 receptor daf-2 mutants, enhanced proteostatic mechanisms are accompanied by elevated intestinal lipid stores, but the role of lipid droplets in longevity has remained obscure. Here, while determining the regulatory network of the selective autophagy receptor SQST-1/SQSTM1, we unexpectedly uncovered a novel role for lipid droplets in proteostasis and longevity. Using an unbiased genome-wide RNAi screening approach, we identified several SQST-1 modulators, including proteins found on lipid droplets and those prone to aggregate with age. SQST-1 accumulated on lipid droplets when autophagy was inhibited, suggesting that lipid droplets may serve a role in facilitating selective autophagy. Expansion of intestinal lipid droplets by silencing the conserved cytosolic triacylglycerol lipase gene atgl-1/ATGL enhanced autophagy, and extended lifespan in an HSF-1/HSF1-dependent and CDC-48/VCP-dependent manner. Silencing atgl-1 mitigated the age-related accumulation of SQST-1 and reduced overall ubiquitination of proteins. Reducing atgl-1 also improved proteostasis in a nematode model of Alzheimer’s disease. Subcellular analyses revealed that lipid droplets unexpectedly harbor more ubiquitinated proteins than the cytosol. Accordingly, low lipid droplet levels exacerbated the proteostatic collapse when autophagy or proteasome function was compromised. Altogether, our study uncovers a key role for lipid droplets in C. elegans as a proteostatic mediator that reduces protein ubiquitination, facilitates autophagy, and promotes longevity.

scholarly journals Two human metabolites rescue a C. elegans model of Alzheimer’s disease via a cytosolic unfolded protein response

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Priyanka Joshi ◽  
Michele Perni ◽  
Ryan Limbocker ◽  
Benedetta Mannini ◽  
Sam Casford ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Unfolded Protein Response ◽  
Neurodegenerative Disorders ◽  
C Elegans ◽  
Unfolded Protein ◽  
Model Of Alzheimer’S Disease ◽  
Age Related ◽  
Parkinson’S Diseases ◽  
Protein Response

AbstractAge-related changes in cellular metabolism can affect brain homeostasis, creating conditions that are permissive to the onset and progression of neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. Although the roles of metabolites have been extensively studied with regard to cellular signaling pathways, their effects on protein aggregation remain relatively unexplored. By computationally analysing the Human Metabolome Database, we identified two endogenous metabolites, carnosine and kynurenic acid, that inhibit the aggregation of the amyloid beta peptide (Aβ) and rescue a C. elegans model of Alzheimer’s disease. We found that these metabolites act by triggering a cytosolic unfolded protein response through the transcription factor HSF-1 and downstream chaperones HSP40/J-proteins DNJ-12 and DNJ-19. These results help rationalise previous observations regarding the possible anti-ageing benefits of these metabolites by providing a mechanism for their action. Taken together, our findings provide a link between metabolite homeostasis and protein homeostasis, which could inspire preventative interventions against neurodegenerative disorders.

Does Declining Mitochondrial NAD+ and Unscheduled Opening of Mitochondrial Transition Pore Promote Mammalian Aging?

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. SCI-3-SCI-3
Author(s):  
David Sinclair ◽  
Angela V. Hafner ◽  
Ana Gomes ◽  
Jing Liang ◽  
Yana Cen ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Memory Deficits ◽  
Dependent Manner ◽  
Advisory Committees ◽  
Model Of Alzheimer’S Disease ◽  
Age Related ◽  
Promote Cell Survival ◽  
Mitochondrial Defects ◽  
Equity Ownership ◽  
Mitochondrial Transition Pore

Abstract Abstract SCI-3 The processes that lead to the susceptibility of post-mitotic tissues to diseases of aging are poorly understood, but mitochondria are considered a key regulator. SIRT3 is mitochondrial sirtuin, a member a family of NAD+-dependent deacetylases. We have previously shown that increased levels of NAD+ in mitochondria promote cell survival in a SIRT3-dependent manner, but how this protection is mediated is unknown. Here we show that mitochondrial NAD+ levels decline dramatically with age and that SIRT3 is a critical component and regulator of the mitochondrial transition pore (MTP). Mice lacking SIRT3 exhibit hyperacetylation of the MTP with age, and as a result, develop multiple defects in post-mitotic tissues as they age, including mitochondrial defects, susceptibility to cardiac failure, and learning and memory deficits. In a mouse model of Alzheimer's disease (AD), SIRT3 knockout mice show striking phenotypes including small size, kyphosis, and a markedly reduced lifespan. Similar to mice, human brain samples show that acetylation of the MTP increases with age and with AD. These findings indicate that declining NAD levels with age lead to memory deficits and accelerate age-related diseases in post-mitotic tissues due to a decline in SIRT3 activity and unscheduled opening of the MTP. Disclosures: Sinclair: GlaxoSmithKline: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

scholarly journals Specific regulation of thermosensitive lipid droplet fusion by a nuclear hormone receptor pathway

2017 ◽  
Vol 114 (33) ◽  
pp. 8841-8846 ◽  
Author(s):  
Shiwei Li ◽  
Qi Li ◽  
Yuanyuan Kong ◽  
Shuang Wu ◽  
Qingpo Cui ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Lipid Droplets ◽  
Nuclear Hormone Receptor ◽  
Dependent Manner ◽  
Hormone Synthesis ◽  
C Elegans ◽  
Human Cytochrome ◽  
Specific Regulation ◽  
Regulatory Functions

Nuclear receptors play important roles in regulating fat metabolism and energy production in humans. The regulatory functions and endogenous ligands of many nuclear receptors are still unidentified, however. Here, we report that CYP-37A1 (ortholog of human cytochrome P450 CYP4V2), EMB-8 (ortholog of human P450 oxidoreductase POR), and DAF-12 (homolog of human nuclear receptors VDR/LXR) constitute a hormone synthesis and nuclear receptor pathway in Caenorhabditis elegans. This pathway specifically regulates the thermosensitive fusion of fat-storing lipid droplets. CYP-37A1, together with EMB-8, synthesizes a lipophilic hormone not identical to Δ7-dafachronic acid, which represses the fusion-promoting function of DAF-12. CYP-37A1 also negatively regulates thermotolerance and lifespan at high temperature in a DAF-12–dependent manner. Human CYP4V2 can substitute for CYP-37A1 in C. elegans. This finding suggests the existence of a conserved CYP4V2-POR–nuclear receptor pathway that functions in converting multilocular lipid droplets to unilocular ones in human cells; misregulation of this pathway may lead to pathogenic fat storage.

scholarly journals The autophagy receptor p62/SQST-1 promotes proteostasis and longevity in C. elegans by inducing autophagy

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Caroline Kumsta ◽  
Jessica T. Chang ◽  
Reina Lee ◽  
Ee Phie Tan ◽  
Yongzhi Yang ◽  
...  
Keyword(s):  
Heat Shock ◽  
Stress Responses ◽  
Dependent Manner ◽  
Selective Autophagy ◽  
C Elegans ◽  
Proteotoxic Stress ◽  
Autophagy Induction ◽  
The Impact ◽  
Lifespan Regulation

AbstractAutophagy can degrade cargos with the help of selective autophagy receptors such as p62/SQSTM1, which facilitates the degradation of ubiquitinated cargo. While the process of autophagy has been linked to aging, the impact of selective autophagy in lifespan regulation remains unclear. We have recently shown in Caenorhabditis elegans that transcript levels of sqst-1/p62 increase upon a hormetic heat shock, suggesting a role of SQST-1/p62 in stress response and aging. Here, we find that sqst-1/p62 is required for hormetic benefits of heat shock, including longevity, improved neuronal proteostasis, and autophagy induction. Furthermore, overexpression of SQST-1/p62 is sufficient to induce autophagy in distinct tissues, extend lifespan, and improve the fitness of mutants with defects in proteostasis in an autophagy-dependent manner. Collectively, these findings illustrate that increased expression of a selective autophagy receptor is sufficient to induce autophagy, enhance proteostasis and extend longevity, and demonstrate an important role for sqst-1/p62 in proteotoxic stress responses.

scholarly journals Hsp90 Stabilizes SIRT1 Orthologs in Mammalian Cells and C. elegans

2018 ◽  
Vol 19 (11) ◽  
pp. 3661 ◽  
Author(s):  
Minh Nguyen ◽  
Milán Somogyvári ◽  
Csaba Sőti
Keyword(s):  
Stress Responses ◽  
Mammalian Cells ◽  
Proteasomal Degradation ◽  
Sirtuin 1 ◽  
Physical Interaction ◽  
Dependent Manner ◽  
Hsp90 Inhibition ◽  
C Elegans ◽  
Age Related ◽  
Hsp 90

Sirtuin 1 (SIRT1) othologs are ubiquitous NAD+-dependent deacetylases that act as nutrient sensors and modulate metabolism and stress responses in diverse organisms. Both mammalian SIRT1 and Caenorhabditis elegans SIR-2.1 have been implicated in dietary restriction, longevity, and healthspan. Hsp90 is an evolutionarily conserved molecular chaperone that stabilizes a plethora of signaling ’client’ proteins and regulates fundamental biological processes. Here we report that Hsp90 is required for conformational stabilization of SIRT1 and SIR-2.1. We find that inhibition of Hsp90 by geldanamycin (GA) induces the depletion of mammalian SIRT1 protein in a concentration and time dependent manner in COS-7 and HepG2 cells. In contrast to SIRT1, SIRT2 level remains unchanged by GA treatment, reflecting a specific Hsp90 SIRT1 interaction. Hsp90 inhibition leads to the destabilization and proteasomal degradation of SIRT1. Moreover, we observe a GA-sensitive physical interaction between SIRT1 and Hsp90 by immunoprecipitation. We also demonstrate that hsp-90 gene silencing also induces SIR-2.1 protein depletion and proteasomal degradation in C. elegans. Our findings identify metazoan SIRT1 orthologs as Hsp90 clients and reveal a novel crosstalk between the proteostasis and nutrient signaling networks, which may have implications in various age related diseases.

scholarly journals Glucose increases the lifespan of post-reproductive C. elegans independently of FOXO

2018 ◽  
Author(s):  
Wang Lei ◽  
Caroline Beaudoin-Chabot ◽  
Guillaume Thibault
Keyword(s):  
Er Stress ◽  
Stress Resistance ◽  
Metabolic Diseases ◽  
Strong Association ◽  
Cellular Damage ◽  
Model Organisms ◽  
Dependent Manner ◽  
C Elegans ◽  
Age Related ◽  
Er Homeostasis

ABSTRACTAging is one of the most critical risk factors for the development of metabolic syndromes1. Prominent metabolic diseases, namely type 2 diabetes and insulin resistance, have a strong association with endoplasmic reticulum (ER) stress2. Upon ER stress, the unfolded protein response (UPR) is activated to limit cellular damage by adapting to stress conditions and restoring ER homeostasis3,4. However, adaptive genes upregulated from the UPR tend to decrease with age5. Although stress resistance correlates with increased longevity in a variety of model organisms, the links between the UPR, ER stress resistance, and longevity remain poorly understood. Here, we show that supplementing bacteria diet with 2% glucose (high glucose diet, HGD) in post-reproductive 7-day-old (7DO) C. elegans significantly extend their lifespan in contrast to shortening the lifespan of reproductive 3-day-old (3DO) animals. The insulin-IGF receptor DAF-2 and its immediate downstream target, phosphoinositide 3-kinase (PI3K) AGE-1, were found to be critical factors in extending the lifespan of 7DO worms on HGD. The downstream transcription factor forkhead box O (FOXO) DAF-16 did not extend the lifespan of 7DO worms on HGD in contrast of its previously reported role in modulating lifespan of 3DO worms6. Furthermore, we identified that UPR activation through the highly conserved ATF-6 and PEK-1 sensors significantly extended the longevity of 7DO worms on HGD but not through the IRE-1 sensor. Our results demonstrate that HGD extends lifespan of post-reproductive worms in a UPR-dependent manner but independently of FOXO. Based on these observations, we hypothesise that HGD activates the otherwise quiescent UPR in aged worms to overcome age-related stress and to restore ER homeostasis. In contrast, young adult animals subjected to HGD leads to unresolved ER stress, conversely leading to a deleterious stress response.

scholarly journals Crosstalk between Different DNA Repair Pathways Contributes to Neurodegenerative Diseases

Biology ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 163
Author(s):  
Swapnil Gupta ◽  
Panpan You ◽  
Tanima SenGupta ◽  
Hilde Nilsen ◽  
Kulbhushan Sharma
Keyword(s):  
Dna Repair ◽  
Neurodegenerative Diseases ◽  
3D Models ◽  
Model Systems ◽  
Spinocerebellar Ataxias ◽  
C Elegans ◽  
Cellular Processes ◽  
Age Related ◽  
Damage Response ◽  
Lateral Sclerosis

Genomic integrity is maintained by DNA repair and the DNA damage response (DDR). Defects in certain DNA repair genes give rise to many rare progressive neurodegenerative diseases (NDDs), such as ocular motor ataxia, Huntington disease (HD), and spinocerebellar ataxias (SCA). Dysregulation or dysfunction of DDR is also proposed to contribute to more common NDDs, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and Amyotrophic Lateral Sclerosis (ALS). Here, we present mechanisms that link DDR with neurodegeneration in rare NDDs caused by defects in the DDR and discuss the relevance for more common age-related neurodegenerative diseases. Moreover, we highlight recent insight into the crosstalk between the DDR and other cellular processes known to be disturbed during NDDs. We compare the strengths and limitations of established model systems to model human NDDs, ranging from C. elegans and mouse models towards advanced stem cell-based 3D models.

scholarly journals Steroid hormones sulfatase inactivation extends lifespan and ameliorates age-related diseases

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Mercedes M. Pérez-Jiménez ◽  
José M. Monje-Moreno ◽  
Ana María Brokate-Llanos ◽  
Mónica Venegas-Calerón ◽  
Alicia Sánchez-García ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Caenorhabditis Elegans ◽  
Protein Aggregation ◽  
Steroid Hormones ◽  
Sensory Neurons ◽  
Environmental Cues ◽  
Steroid Sulfatase ◽  
Loss Of Function ◽  
C Elegans ◽  
Age Related

AbstractAging and fertility are two interconnected processes. From invertebrates to mammals, absence of the germline increases longevity. Here we show that loss of function of sul-2, the Caenorhabditis elegans steroid sulfatase (STS), raises the pool of sulfated steroid hormones, increases longevity and ameliorates protein aggregation diseases. This increased longevity requires factors involved in germline-mediated longevity (daf-16, daf-12, kri-1, tcer-1 and daf-36 genes) although sul-2 mutations do not affect fertility. Interestingly, sul-2 is only expressed in sensory neurons, suggesting a regulation of sulfated hormones state by environmental cues. Treatment with the specific STS inhibitor STX64, as well as with testosterone-derived sulfated hormones reproduces the longevity phenotype of sul-2 mutants. Remarkably, those treatments ameliorate protein aggregation diseases in C. elegans, and STX64 also Alzheimer’s disease in a mammalian model. These results open the possibility of reallocating steroid sulfatase inhibitors or derivates for the treatment of aging and aging related diseases.

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