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.

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.

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 Sirtuins and Autophagy in Age-Associated Neurodegenerative Diseases: Lessons from the C. elegans Model

2021 ◽  
Vol 22 (22) ◽  
pp. 12263
Author(s):  
Anam Naseer ◽  
Snober Shabnam Mir ◽  
Krisztina Takacs-Vellai ◽  
Aamir Nazir
Keyword(s):  
Neurodegenerative Diseases ◽  
Histone Deacetylases ◽  
Vital Role ◽  
Model System ◽  
Dependent Manner ◽  
Class Iii ◽  
C Elegans ◽  
Cell Death Pathways ◽  
Protein Clearance ◽  
Multiple Processes

Age-associated neurodegenerative diseases are known to have “impaired protein clearance” as one of the key features causing their onset and progression. Hence, homeostasis is the key to maintaining balance throughout the cellular system as an organism ages. Any imbalance in the protein clearance machinery is responsible for accumulation of unwanted proteins, leading to pathological consequences—manifesting in neurodegeneration and associated debilitating outcomes. Multiple processes are involved in regulating this phenomenon; however, failure to regulate the autophagic machinery is a critical process that hampers the protein clearing pathway, leading to neurodegeneration. Another important and widely known component that plays a role in modulating neurodegeneration is a class of proteins called sirtuins. These are class III histone deacetylases (HDACs) that are known to regulate various vital processes such as longevity, genomic stability, transcription and DNA repair. These enzymes are also known to modulate neurodegeneration in an autophagy-dependent manner. Considering its genetic relevance and ease of studying disease-related endpoints in neurodegeneration, the model system Caenorhabditis elegans has been successfully employed in deciphering various functional outcomes related to critical protein molecules, cell death pathways and their association with ageing. This review summarizes the vital role of sirtuins and autophagy in ageing and neurodegeneration, in particular highlighting the knowledge obtained using the C. elegans model system.

scholarly journals AMPK Modulates Associative Learning via Neuronal Mitochondrial Fusion in C. elegans

2020 ◽  
Author(s):  
Caroline C. Escoubas ◽  
Vanessa Laversenne ◽  
Emina Tabakovic ◽  
Heather J. Weir ◽  
Nicole Clark ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Associative Learning ◽  
Therapeutic Option ◽  
Mitochondrial Fusion ◽  
Ampk Activation ◽  
Neuronal Function ◽  
Learning Capacity ◽  
C Elegans ◽  
Mitochondrial Homeostasis ◽  
Age Related

ABSTRACTLoss of metabolic homeostasis is one of the hallmarks of the aging process that might contribute to pathogenesis by creating a permissive landscape over which neurodegenerative diseases can take hold. AMPK, a conserved energy sensor, extends lifespan and is protective in some neurodegenerative models. AMPK regulates mitochondrial homeostasis and morphology, however, whether mitochondrial regulation causally links AMPK to protection against loss of neuronal function with aging and diseases remains unclear. Here we use an associative learning protocol in C. elegans as a readout of neuronal function and show that AMPK activation enhances associative learning and prevents age-related loss of learning capacity. AMPK promotes neuronal mitochondrial fusion and mitochondrial fragmentation via fzo-1 deletion blocks AMPK’s effects on associative learning. Restoring mitochondrial fusion capacity specifically in the neurons rescued learning capacity downstream of AMPK. Finally, AMPK activation rescues neuronal Aβ1-42 induced loss of associative learning. Overall, our results suggest that targeting neuronal metabolic flexibility may be a viable therapeutic option to restore neuronal function in the context of aging and neurodegenerative diseases.

scholarly journals Trigonelline Extends the Lifespan of C. Elegans and Delays the Progression of Age-Related Diseases by Activating AMPK, DAF-16, and HSF-1

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Wen-Yu Zeng ◽  
Lin Tan ◽  
Cong Han ◽  
Zhuo-Ya Zheng ◽  
Gui-Sheng Wu ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Neurodegenerative Diseases ◽  
Stress Resistance ◽  
Aging Effect ◽  
Loss Of Function ◽  
Asian Countries ◽  
C Elegans ◽  
Age Related ◽  
Anti Oxidant ◽  
Pathogenic Effects

Trigonelline is the main alkaloid with bioactivity presented in fenugreek, which was used in traditional medicine in Asian countries for centuries. It is reported that trigonelline has anti-inflammatory, anti-oxidant, and anti-pathogenic effects. We are wondering whether trigonelline have anti-aging effect. We found that 50 μM of trigonelline had the best anti-aging activity and could prolong the lifespan of Caenorhabditis elegans (C. elegans) by about 17.9%. Trigonelline can enhance the oxidative, heat, and pathogenic stress resistance of C. elegans. Trigonelline could also delay the development of neurodegenerative diseases, such as AD, PD, and HD, in models of C. elegans. Trigonelline could not prolong the lifespan of long-lived worms with loss-of-function mutations in genes regulating energy and nutrition, such as clk-1, isp-1, eat-2, and rsks-1. Trigonelline requires daf-16, hsf-1, and aak-2 to extend the lifespan of C. elegans. Trigonelline can also up-regulate the expression of daf-16 and hsf-1 targeted downstream genes, such as sod-3, gst-4, hsp-16.1, and hsp-12.6. Our results can be the basis for developing trigonelline-rich products with health benefits, as well as for further research on the pharmacological usage of trigonelline.

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.

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