scholarly journals Small Molecule Stabilization of PINK-1/PINK1 Improves Neurodegenerative Disease

2021 ◽  
Author(s):  
Elissa Tjahjono ◽  
Jingqi Pei ◽  
Alexey V Revtovich ◽  
Terri-Jeanne E Liu ◽  
Alisha Swadi ◽  
...  
Keyword(s):  
Neurodegenerative Disease ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Mitochondrial Fragmentation ◽  
Atp Production ◽  
C Elegans ◽  
Mitochondrial Homeostasis ◽  
Phenotypic Screen ◽  
Gfp Reporter ◽  
Common Causes

Macroautophagic recycling of dysfunctional mitochondria, known as mitophagy, is essential for mitochondrial homeostasis and cell viability. Accumulation of defective mitochondria and impaired mitophagy have been widely implicated in many neurodegenerative diseases, and loss-of-function mutations of two regulators of mitophagy, PINK1 and Parkin, are amongst the most common causes of recessive Parkinson's disease. Activation of mitophagy via pharmacological treatments may be a feasible approach for combating neurodegeneration. In this effort, we screened ~45,000 small molecules for the ability to activate mitophagy. A high-throughput, whole-organism, phenotypic screen was conducted by monitoring stabilization of PINK-1/PINK1, a key event in mitophagy activation, in a Caenorhabditis elegans strain carrying a Ppink-1::PINK-1::GFP reporter. We obtained eight hits that induced mitophagy, as evidenced by increased mitochondrial fragmentation and autophagosome formation. Several of the compounds also reduced ATP production, oxygen consumption, mitochondrial mass, and/or mitochondrial membrane potential. Importantly, we found that treatment with two compounds, which we named PS83 and PS106 (more commonly known as sertraline) reduced neurodegenerative disease phenotypes (including delayed paralysis in a C. elegans Alzheimer's model) in a PINK-1/PINK1-dependent manner. This report presents a promising step toward the identification of compounds that will stimulate mitochondrial turnover.

scholarly journals Mitochondria-affecting small molecules ameliorate proteostasis defects associated with neurodegenerative diseases

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Elissa Tjahjono ◽  
Jingqi Pei ◽  
Alexey V. Revtovich ◽  
Terri-Jeanne E. Liu ◽  
Alisha Swadi ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Small Molecules ◽  
Protein A ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Atp Production ◽  
C Elegans ◽  
Mitochondrial Homeostasis ◽  
Phenotypic Screen ◽  
Common Causes

AbstractMacroautophagic recycling of dysfunctional mitochondria, known as mitophagy, is essential for mitochondrial homeostasis and cell viability. Accumulation of defective mitochondria and impaired mitophagy have been widely implicated in many neurodegenerative diseases, and loss-of-function mutations of PINK1 and Parkin, two key regulators of mitophagy, are amongst the most common causes of heritable parkinsonism. This has led to the hypothesis that pharmacological stimulation of mitophagy may be a feasible approach to combat neurodegeneration. Toward this end, we screened ~ 45,000 small molecules using a high-throughput, whole-organism, phenotypic screen that monitored accumulation of PINK-1 protein, a key event in mitophagic activation, in a Caenorhabditis elegans strain carrying a Ppink-1::PINK-1::GFP reporter. We obtained eight hits that increased mitochondrial fragmentation and autophagosome formation. Several of the compounds also reduced ATP production, oxygen consumption, mitochondrial mass, and/or mitochondrial membrane potential. Importantly, we found that treatment with two compounds, which we named PS83 and PS106 (more commonly known as sertraline) reduced neurodegenerative disease phenotypes, including delaying paralysis in a C. elegans β-amyloid aggregation model in a PINK-1-dependent manner. This report presents a promising step toward the identification of compounds that will stimulate mitochondrial turnover.

A Cuticle Collagen Encoded by the lon-3 Gene May Be a Target of TGF-β Signaling in Determining Caenorhabditis elegans Body Shape

Genetics ◽  
2002 ◽  
Vol 162 (4) ◽  
pp. 1631-1639
Author(s):  
Yo Suzuki ◽  
Gail A Morris ◽  
Min Han ◽  
William B Wood
Keyword(s):  
Caenorhabditis Elegans ◽  
Body Shape ◽  
Small Body ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Cellular Mechanisms ◽  
C Elegans ◽  
Gene Expression Analyses ◽  
Dose Dependent

Abstract The signaling pathway initiated by the TGF-β family member DBL-1 in Caenorhabditis elegans controls body shape in a dose-dependent manner. Loss-of-function (lf) mutations in the dbl-1 gene cause a short, small body (Sma phenotype), whereas overexpression of dbl-1 causes a long body (Lon phenotype). To understand the cellular mechanisms underlying these phenotypes, we have isolated suppressors of the Sma phenotype resulting from a dbl-1(lf) mutation. Two of these suppressors are mutations in the lon-3 gene, of which four additional alleles are known. We show that lon-3 encodes a collagen that is a component of the C. elegans cuticle. Genetic and reporter-gene expression analyses suggest that lon-3 is involved in determination of body shape and is post-transcriptionally regulated by the dbl-1 pathway. These results support the possibility that TGF-β signaling controls C. elegans body shape by regulating cuticle composition.

scholarly journals H3K27 modifiers regulate lifespan in C. elegans in a context-dependent manner

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Abigail R. R. Guillermo ◽  
Karolina Chocian ◽  
Gavriil Gavriilidis ◽  
Julien Vandamme ◽  
Anna Elisabetta Salcini ◽  
...  
Keyword(s):  
Lifespan Extension ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Animal Cells ◽  
C Elegans ◽  
Specific Effects ◽  
Aberrant Gene Expression ◽  
Lysine Methyltransferase ◽  
Epigenetic Signatures ◽  
Aberrant Gene

Abstract Background Evidence of global heterochromatin decay and aberrant gene expression in models of physiological and premature ageing have long supported the “heterochromatin loss theory of ageing”, which proposes that ageing is aetiologically linked to, and accompanied by, a progressive, generalised loss of repressive epigenetic signatures. However, the remarkable plasticity of chromatin conformation suggests that the re-establishment of such marks could potentially revert the transcriptomic architecture of animal cells to a “younger” state, promoting longevity and healthspan. To expand our understanding of the ageing process and its connection to chromatin biology, we screened an RNAi library of chromatin-associated factors for increased longevity phenotypes. Results We identified the lysine demethylases jmjd-3.2 and utx-1, as well as the lysine methyltransferase mes-2 as regulators of both lifespan and healthspan in C. elegans. Strikingly, we found that both overexpression and loss of function of jmjd-3.2 and utx-1 are all associated with enhanced longevity. Furthermore, we showed that the catalytic activity of UTX-1, but not JMJD-3.2, is critical for lifespan extension in the context of overexpression. In attempting to reconcile the improved longevity associated with both loss and gain of function of utx-1, we investigated the alternative lifespan pathways and tissue specificity of longevity outcomes. We demonstrated that lifespan extension caused by loss of utx-1 function is daf-16 dependent, while overexpression effects are partially independent of daf-16. In addition, lifespan extension was observed when utx-1 was knocked down or overexpressed in neurons and intestine, whereas in the epidermis, only knockdown of utx-1 conferred improved longevity. Conclusions We show that the regulation of longevity by chromatin modifiers can be the result of the interaction between distinct factors, such as the level and tissue of expression. Overall, we suggest that the heterochromatin loss model of ageing may be too simplistic an explanation of organismal ageing when molecular and tissue-specific effects are taken into account.

scholarly journals Evolutionarily conserved regulation of immunity by the splicing factor RNP-6/PUF60

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Chun Kew ◽  
Wenming Huang ◽  
Julia Fischer ◽  
Raja Ganesan ◽  
Nirmal Robinson ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Bacterial Pathogen ◽  
Active Role ◽  
Suppressive Effect ◽  
Mapk Signaling ◽  
Splicing Factor ◽  
Dependent Manner ◽  
Loss Of Function ◽  
C Elegans ◽  
Evolutionarily Conserved

Splicing is a vital cellular process that modulates important aspects of animal physiology, yet roles in regulating innate immunity are relatively unexplored. From genetic screens in C. elegans, we identified splicing factor RNP-6/PUF60 whose activity suppresses immunity, but promotes longevity, suggesting a tradeoff between these processes. Bacterial pathogen exposure affects gene expression and splicing in a rnp-6 dependent manner, and rnp-6 gain and loss-of-function activities reveal an active role in immune regulation. Another longevity promoting splicing factor, SFA-1, similarly exerts an immuno-suppressive effect, working downstream or parallel to RNP-6. RNP-6 acts through TIR-1/PMK-1/MAPK signaling to modulate immunity. The mammalian homolog, PUF60, also displays anti-inflammatory properties, and its levels swiftly decrease after bacterial infection in mammalian cells, implying a role in the host response. Altogether our findings demonstrate an evolutionarily conserved modulation of immunity by specific components of the splicing machinery.

scholarly journals Dithiothreitol causes toxicity in C. elegans by modulating the methionine-homocysteine cycle

2021 ◽  
Author(s):  
Gokul G ◽  
Jogender Singh
Keyword(s):  
Dependent Manner ◽  
Loss Of Function ◽  
Genetic Studies ◽  
Cellular Physiology ◽  
C Elegans ◽  
Unfolded Protein ◽  
Oxidative Protein Folding ◽  
Dietary Component ◽  
Protein Response ◽  
Redox Reagent

The redox reagent dithiothreitol (DTT) causes stress in the endoplasmic reticulum (ER) by disrupting its oxidative protein folding environment, which results in the accumulation and misfolding of the newly synthesized proteins. DTT may potentially impact cellular physiology by ER-independent mechanisms; however, such mechanisms remain poorly characterized. Using the nematode model Caenorhabditis elegans, here we show that DTT toxicity is modulated by the bacterial diet. Specifically, the dietary component vitamin B12 alleviates DTT toxicity in a methionine synthase-dependent manner. Using a forward genetic screen, we identify that loss-of-function of R08E5.3, an S-adenosylmethionine (SAM)-dependent methyltransferase, imparts resistance to DTT. DTT upregulates R08E5.3 expression and modulates the activity of the methionine-homocysteine cycle. Employing genetic studies, we show that DTT toxicity is a result of the depletion of SAM. Finally, we show that a functional IRE-1/XBP-1 unfolded protein response pathway is required to counteract toxicity at high, but not low, DTT concentrations.

scholarly journals The NALCN Channel Regulator UNC-80 Functions in a Subset of Interneurons To Regulate Caenorhabditis elegans Reversal Behavior

2019 ◽  
Vol 10 (1) ◽  
pp. 199-210 ◽  
Author(s):  
Chuanman Zhou ◽  
Jintao Luo ◽  
Xiaohui He ◽  
Qian Zhou ◽  
Yunxia He ◽  
...  
Keyword(s):  
Plant Hormone ◽  
Neuronal Excitability ◽  
Resting Membrane Potential ◽  
Loss Of Function ◽  
Wild Type ◽  
C Elegans ◽  
Link Type ◽  
Complex Functions ◽  
And Function ◽  
Multiple Loss

NALCN (Na+leak channel, non-selective) is a conserved, voltage-insensitive cation channel that regulates resting membrane potential and neuronal excitability. UNC79 and UNC80 are key regulators of the channel function. However, the behavioral effects of the channel complex are not entirely clear and the neurons in which the channel functions remain to be identified. In a forward genetic screen for C. elegans mutants with defective avoidance response to the plant hormone methyl salicylate (MeSa), we isolated multiple loss-of-function mutations in unc-80 and unc-79. C. elegans NALCN mutants exhibited similarly defective MeSa avoidance. Interestingly, NALCN, unc-80 and unc-79 mutants all showed wild type-like responses to other attractive or repelling odorants, suggesting that NALCN does not broadly affect odor detection or related forward and reversal behaviors. To understand in which neurons the channel functions, we determined the identities of a subset of unc-80-expressing neurons. We found that unc-79 and unc-80 are expressed and function in overlapping neurons, which verified previous assumptions. Neuron-specific transgene rescue and knockdown experiments suggest that the command interneurons AVA and AVE and the anterior guidepost neuron AVG can play a sufficient role in mediating unc-80 regulation of the MeSa avoidance. Though primarily based on genetic analyses, our results further imply that MeSa might activate NALCN by direct or indirect actions. Altogether, we provide an initial look into the key neurons in which the NALCN channel complex functions and identify a novel function of the channel in regulating C. elegans reversal behavior through command interneurons.

scholarly journals Functional Characterization of the Adenylyl Cyclase Genesgs-1by Analysis of a Mutational Spectrum inCaenorhabditis elegans

Genetics ◽  
2002 ◽  
Vol 161 (1) ◽  
pp. 133-142 ◽  
Author(s):  
Celine Moorman ◽  
Ronald H A Plasterk
Keyword(s):  
Life Span ◽  
Adenylyl Cyclase ◽  
Neuronal Degeneration ◽  
Functional Characterization ◽  
Adenylyl Cyclases ◽  
Loss Of Function ◽  
C Elegans ◽  
Larval Stages ◽  
Pharyngeal Pumping

AbstractThe sgs-1 (suppressor of activated Gαs) gene encodes one of the four adenylyl cyclases in the nematode C. elegans and is most similar to mammalian adenylyl cyclase type IX. We isolated a complete loss-of-function mutation in sgs-1 and found it to result in animals with retarded development that arrest in variable larval stages. sgs-1 mutant animals exhibit lethargic movement and pharyngeal pumping and (while not reaching adulthood) have a mean life span that is >50% extended compared to wild type. An extensive set of reduction-of-function mutations in sgs-1 was isolated in a screen for suppressors of a neuronal degeneration phenotype induced by the expression of a constitutively active version of the heterotrimeric Gαs subunit of C. elegans. Although most of these mutations change conserved residues within the catalytic domains of sgs-1, mutations in the less-conserved transmembrane domains are also found. The sgs-1 reduction-of-function mutants are viable and have reduced locomotion rates, but do not show defects in pharyngeal pumping or life span.

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.

scholarly journals glp-3 Is Required for Mitosis and Meiosis in the Caenorhabditis elegans Germ Line

Genetics ◽  
1997 ◽  
Vol 145 (1) ◽  
pp. 111-121 ◽  
Author(s):  
Lisa C Kadyk ◽  
Eric J Lambie ◽  
Judith Kimble
Keyword(s):  
Caenorhabditis Elegans ◽  
Germ Cells ◽  
Germ Line ◽  
Stem Cell Population ◽  
Phenotypic Characterization ◽  
Loss Of Function ◽  
Dapi Staining ◽  
Cell Cycles ◽  
C Elegans ◽  
Mitosis And Meiosis

The germ line is the only tissue in Caenorhabditis elegans in which a stem cell population continues to divide mitotically throughout life; hence the cell cycles of the germ line and the soma are regulated differently. Here we report the genetic and phenotypic characterization of the glp-3 gene. In animals homozygous for each of five recessive loss-of-function alleles, germ cells in both hermaphrodites and males fail to progress through mitosis and meiosis, but somatic cells appear to divide normally. Germ cells in animals grown at 15° appear by DAPI staining to be uniformly arrested at the G2/M transition with <20 germ cells per gonad on average, suggesting a checkpoint-mediated arrest. In contrast, germ cells in mutant animals grown at 25° frequently proliferate slowly during adulthood, eventually forming small germ lines with several hundred germ cells. Nevertheless, cells in these small germ lines never undergo meiosis. Double mutant analysis with mutations in other genes affecting germ cell proliferation supports the idea that glp-3 may encode a gene product that is required for the mitotic and meiotic cell cycles in the C. elegans germ line.

scholarly journals The Parkinson’s Disease-Associated Protein DJ-1 Protects Dictyostelium Cells from AMPK-Dependent Outcomes of Oxidative Stress

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1874
Author(s):  
Suwei Chen ◽  
Sarah J. Annesley ◽  
Rasha A. F. Jasim ◽  
Paul R. Fisher
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Respiration ◽  
Cysteine Residue ◽  
Reduced Form ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Cellular Pathology

Mitochondrial dysfunction has been implicated in the pathology of Parkinson’s disease (PD). In Dictyostelium discoideum, strains with mitochondrial dysfunction present consistent, AMPK-dependent phenotypes. This provides an opportunity to investigate if the loss of function of specific PD-associated genes produces cellular pathology by causing mitochondrial dysfunction with AMPK-mediated consequences. DJ-1 is a PD-associated, cytosolic protein with a conserved oxidizable cysteine residue that is important for the protein’s ability to protect cells from the pathological consequences of oxidative stress. Dictyostelium DJ-1 (encoded by the gene deeJ) is located in the cytosol from where it indirectly inhibits mitochondrial respiration and also exerts a positive, nonmitochondrial role in endocytosis (particularly phagocytosis). Its loss in unstressed cells impairs endocytosis and causes correspondingly slower growth, while also stimulating mitochondrial respiration. We report here that oxidative stress in Dictyostelium cells inhibits mitochondrial respiration and impairs phagocytosis in an AMPK-dependent manner. This adds to the separate impairment of phagocytosis caused by DJ-1 knockdown. Oxidative stress also combines with DJ-1 loss in an AMPK-dependent manner to impair or exacerbate defects in phototaxis, morphogenesis and growth. It thereby phenocopies mitochondrial dysfunction. These results support a model in which the oxidized but not the reduced form of DJ-1 inhibits AMPK in the cytosol, thereby protecting cells from the adverse consequences of oxidative stress, mitochondrial dysfunction and the resulting AMPK hyperactivity.

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