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1.
Cell ; 186(4): 786-802.e28, 2023 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-36754049

RESUMO

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that results from many diverse genetic causes. Although therapeutics specifically targeting known causal mutations may rescue individual types of ALS, these approaches cannot treat most cases since they have unknown genetic etiology. Thus, there is a pressing need for therapeutic strategies that rescue multiple forms of ALS. Here, we show that pharmacological inhibition of PIKFYVE kinase activates an unconventional protein clearance mechanism involving exocytosis of aggregation-prone proteins. Reducing PIKFYVE activity ameliorates ALS pathology and extends survival of animal models and patient-derived motor neurons representing diverse forms of ALS including C9ORF72, TARDBP, FUS, and sporadic. These findings highlight a potential approach for mitigating ALS pathogenesis that does not require stimulating macroautophagy or the ubiquitin-proteosome system.


Assuntos
Esclerose Lateral Amiotrófica , Fosfatidilinositol 3-Quinases , Animais , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Neurônios Motores , Mutação , Proteína FUS de Ligação a RNA/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Modelos Animais de Doenças
2.
Hum Mol Genet ; 31(19): 3313-3324, 2022 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-35594544

RESUMO

Axonal degeneration is observed in early stages of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). This degeneration generally precedes apoptosis and therefore may be a promising therapeutic target. An increasing number of genes have been identified to actively regulate axonal degeneration and regeneration; however, only a few potential therapeutic targets have been identified in the context of neurodegenerative diseases. Here we investigate DLK-1, a major axonal regeneration pathway and its contribution to axonal degeneration phenotypes in several Caenorhabditis elegans ALS models. From this pathway, we identified the poly (ADP-ribose) (PAR) polymerases (PARP) PARP-1 and PARP-2 as the most consistent modifiers of axonal degeneration in our models of ALS. Genetic and pharmacological inhibition of PARP-1 and PARP-2 reduces axonal degeneration and improves related motor phenotypes.


Assuntos
Esclerose Lateral Amiotrófica , Proteínas de Caenorhabditis elegans , Doenças Neurodegenerativas , Difosfato de Adenosina , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , MAP Quinase Quinase Quinases , Doenças Neurodegenerativas/metabolismo , Poli Adenosina Difosfato Ribose/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Ribose
3.
Proc Natl Acad Sci U S A ; 118(25)2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34140407

RESUMO

In 2006, GRN mutations were first linked to frontotemporal dementia (FTD), the leading cause of non-Alzheimer dementias. While much research has been dedicated to understanding the genetic causes of the disease, our understanding of the mechanistic impacts of GRN deficiency has only recently begun to take shape. With no known cure or treatment available for GRN-related FTD, there is a growing need to rapidly advance genetic and/or small-molecule therapeutics for this disease. This issue is complicated by the fact that, while lysosomal dysfunction seems to be a key driver of pathology, the mechanisms linking a loss of GRN to a pathogenic state remain unclear. In our attempt to address these key issues, we have turned to the nematode, Caenorhabditis elegans, to model, study, and find potential therapies for GRN-deficient FTD. First, we show that the loss of the nematode GRN ortholog, pgrn-1, results in several behavioral and molecular defects, including lysosomal dysfunction and defects in autophagic flux. Our investigations implicate the sphingolipid metabolic pathway in the regulation of many of the in vivo defects associated with pgrn-1 loss. Finally, we utilized these nematodes as an in vivo tool for high-throughput drug screening and identified two small molecules with potential therapeutic applications against GRN/pgrn-1 deficiency. These compounds reverse the biochemical, cellular, and functional phenotypes of GRN deficiency. Together, our results open avenues for mechanistic and therapeutic research into the outcomes of GRN-related neurodegeneration, both genetic and molecular.


Assuntos
Autofagia/genética , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Lisossomos/genética , Progranulinas/metabolismo , Acetofenonas/farmacologia , Animais , Benzopiranos/farmacologia , Vias Biossintéticas , Caenorhabditis elegans/citologia , Proteínas de Caenorhabditis elegans/genética , Avaliação Pré-Clínica de Medicamentos , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Mutação/genética , Fenótipo , Progranulinas/genética , Rivastigmina/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Esfingolipídeos/metabolismo
4.
EMBO Rep ; 22(6): e50958, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-33900016

RESUMO

Mutations in the chromatin remodeller-coding gene CHD7 cause CHARGE syndrome (CS). CS features include moderate to severe neurological and behavioural problems, clinically characterized by intellectual disability, attention-deficit/hyperactivity disorder and autism spectrum disorder. To investigate the poorly characterized neurobiological role of CHD7, we here generate a zebrafish chd7-/- model. chd7-/- mutants have less GABAergic neurons and exhibit a hyperactivity behavioural phenotype. The GABAergic neuron defect is at least in part due to downregulation of the CHD7 direct target gene paqr3b, and subsequent upregulation of MAPK/ERK signalling, which is also dysregulated in CHD7 mutant human cells. Through a phenotype-based screen in chd7-/- zebrafish and Caenorhabditis elegans, we show that the small molecule ephedrine restores normal levels of MAPK/ERK signalling and improves both GABAergic defects and behavioural anomalies. We conclude that chd7 promotes paqr3b expression and that this is required for normal GABAergic network development. This work provides insight into the neuropathogenesis associated with CHD7 deficiency and identifies a promising compound for further preclinical studies.


Assuntos
Transtorno do Espectro Autista , Animais , Caenorhabditis elegans , Cromatina , DNA Helicases , Proteínas de Ligação a DNA/genética , Neurônios GABAérgicos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Membrana , Mutação , Peixe-Zebra
5.
Nature ; 542(7641): 367-371, 2017 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-28178240

RESUMO

The toxicity of misfolded proteins and mitochondrial dysfunction are pivotal factors that promote age-associated functional neuronal decline and neurodegenerative disease. Accordingly, neurons invest considerable cellular resources in chaperones, protein degradation, autophagy and mitophagy to maintain proteostasis and mitochondrial quality. Complicating the challenges of neuroprotection, misfolded human disease proteins and mitochondria can move into neighbouring cells via unknown mechanisms, which may promote pathological spread. Here we show that adult neurons from Caenorhabditis elegans extrude large (approximately 4 µm) membrane-surrounded vesicles called exophers that can contain protein aggregates and organelles. Inhibition of chaperone expression, autophagy or the proteasome, in addition to compromising mitochondrial quality, enhances the production of exophers. Proteotoxically stressed neurons that generate exophers subsequently function better than similarly stressed neurons that did not produce exophers. The extruded exopher transits through surrounding tissue in which some contents appear degraded, but some non-degradable materials can subsequently be found in more remote cells, suggesting secondary release. Our observations suggest that exopher-genesis is a potential response to rid cells of neurotoxic components when proteostasis and organelle function are challenged. We propose that exophers are components of a conserved mechanism that constitutes a fundamental, but formerly unrecognized, branch of neuronal proteostasis and mitochondrial quality control, which, when dysfunctional or diminished with age, might actively contribute to pathogenesis in human neurodegenerative disease and brain ageing.


Assuntos
Caenorhabditis elegans/metabolismo , Micropartículas Derivadas de Células/metabolismo , Mitocôndrias/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Neuroproteção/fisiologia , Agregados Proteicos , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Autofagia , Caenorhabditis elegans/citologia , Citoplasma/metabolismo , Chaperonas Moleculares/metabolismo , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Oxirredução , Complexo de Endopeptidases do Proteassoma/metabolismo
6.
Brain ; 144(11): 3461-3476, 2021 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-34115105

RESUMO

TDP-43 nuclear depletion and concurrent cytoplasmic accumulation in vulnerable neurons is a hallmark feature of progressive neurodegenerative proteinopathies such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cellular stress signalling and stress granule dynamics are now recognized to play a role in ALS/FTD pathogenesis. Defective stress granule assembly is associated with increased cellular vulnerability and death. Ras-GAP SH3-domain-binding protein 1 (G3BP1) is a critical stress granule assembly factor. Here, we define that TDP-43 stabilizes G3BP1 transcripts via direct binding of a highly conserved cis regulatory element within the 3' untranslated region. Moreover, we show in vitro and in vivo that nuclear TDP-43 depletion is sufficient to reduce G3BP1 protein levels. Finally, we establish that G3BP1 transcripts are reduced in ALS/FTD patient neurons bearing TDP-43 cytoplasmic inclusions/nuclear depletion. Thus, our data indicate that, in ALS/FTD, there is a compromised stress granule response in disease-affected neurons due to impaired G3BP1 mRNA stability caused by TDP-43 nuclear depletion. These data implicate TDP-43 and G3BP1 loss of function as contributors to disease.


Assuntos
Esclerose Lateral Amiotrófica/metabolismo , DNA Helicases/metabolismo , Proteínas de Ligação a DNA/metabolismo , Demência Frontotemporal/metabolismo , Neurônios/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , RNA Helicases/metabolismo , Proteínas com Motivo de Reconhecimento de RNA/metabolismo , Esclerose Lateral Amiotrófica/patologia , Células Cultivadas , Demência Frontotemporal/patologia , Humanos , Neurônios/patologia , RNA Mensageiro
7.
PLoS Genet ; 14(9): e1007561, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30192747

RESUMO

Nicotinamide N-methyl-transferase (NNMT) is an essential contributor to various metabolic and epigenetic processes, including the regulating of aging, cellular stress response, and body weight gain. Epidemiological studies show that NNMT is a risk factor for psychiatric diseases like schizophrenia and neurodegeneration, especially Parkinson's disease (PD), but its neuronal mechanisms of action remain obscure. Here, we describe the role of neuronal NNMT using C. elegans. We discovered that ANMT-1, the nematode NNMT ortholog, competes with the methyltransferase LCMT-1 for methyl groups from S-adenosyl methionine. Thereby, it regulates the catalytic capacities of LCMT-1, targeting NPRL-2, a regulator of autophagy. Autophagy is a core cellular, catabolic process for degrading cytoplasmic material, but very little is known about the regulation of autophagy during aging. We report an important role for NNMT in regulation of autophagy during aging, where high neuronal ANMT-1 activity induces autophagy via NPRL-2, which maintains neuronal function in old wild type animals and various disease models, also affecting longevity. In younger animals, however, ANMT-1 activity disturbs neuronal homeostasis and dopamine signaling, causing abnormal behavior. In summary, we provide fundamental insights into neuronal NNMT/ANMT-1 as pivotal regulator of behavior, neurodegeneration, and lifespan by controlling neuronal autophagy, potentially influencing PD and schizophrenia risk in humans.


Assuntos
Comportamento Animal/fisiologia , Proteínas de Caenorhabditis elegans/fisiologia , Caenorhabditis elegans/fisiologia , Longevidade/fisiologia , Nicotinamida N-Metiltransferase/fisiologia , Animais , Animais Geneticamente Modificados , Autofagia/fisiologia , Proteínas de Caenorhabditis elegans/genética , Modelos Animais de Doenças , Dopamina/metabolismo , Humanos , Metiltransferases/metabolismo , Mutagênese Sítio-Dirigida , Doenças Neurodegenerativas/patologia , Neurônios/fisiologia , Nicotinamida N-Metiltransferase/genética , S-Adenosilmetionina/metabolismo
8.
Am J Hum Genet ; 98(5): 1038-1046, 2016 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-27153400

RESUMO

Hereditary spastic paraplegia (HSP) is a genetically and clinically heterogeneous disease characterized by spasticity and weakness of the lower limbs with or without additional neurological symptoms. Although more than 70 genes and genetic loci have been implicated in HSP, many families remain genetically undiagnosed, suggesting that other genetic causes of HSP are still to be identified. HSP can be inherited in an autosomal-dominant, autosomal-recessive, or X-linked manner. In the current study, we performed whole-exome sequencing to analyze a total of nine affected individuals in three families with autosomal-recessive HSP. Rare homozygous and compound-heterozygous nonsense, missense, frameshift, and splice-site mutations in CAPN1 were identified in all affected individuals, and sequencing in additional family members confirmed the segregation of these mutations with the disease (spastic paraplegia 76 [SPG76]). CAPN1 encodes calpain 1, a protease that is widely present in the CNS. Calpain 1 is involved in synaptic plasticity, synaptic restructuring, and axon maturation and maintenance. Three models of calpain 1 deficiency were further studied. In Caenorhabditis elegans, loss of calpain 1 function resulted in neuronal and axonal dysfunction and degeneration. Similarly, loss-of-function of the Drosophila melanogaster ortholog calpain B caused locomotor defects and axonal anomalies. Knockdown of calpain 1a, a CAPN1 ortholog in Danio rerio, resulted in abnormal branchiomotor neuron migration and disorganized acetylated-tubulin axonal networks in the brain. The identification of mutations in CAPN1 in HSP expands our understanding of the disease causes and potential mechanisms.


Assuntos
Axônios/patologia , Calpaína/genética , Predisposição Genética para Doença/genética , Neurônios Motores/patologia , Paraplegia Espástica Hereditária/genética , Adulto , Animais , Encéfalo/fisiologia , Caenorhabditis elegans/genética , Movimento Celular/genética , Modelos Animais de Doenças , Drosophila melanogaster/genética , Feminino , Humanos , Masculino , Neurônios Motores/citologia , Adulto Jovem , Peixe-Zebra/genética
9.
Hum Mol Genet ; 25(6): 1088-99, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26744324

RESUMO

Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative diseases causing progressive gait dysfunction. Over 50 genes have now been associated with HSP. Despite the recent explosion in genetic knowledge, HSP remains without pharmacological treatment. Loss-of-function mutation of the SPAST gene, also known as SPG4, is the most common cause of HSP in patients. SPAST is conserved across animal species and regulates microtubule dynamics. Recent studies have shown that it also modulates endoplasmic reticulum (ER) stress. Here, utilizing null SPAST homologues in C. elegans, Drosophila and zebrafish, we tested FDA-approved compounds known to modulate ER stress in order to ameliorate locomotor phenotypes associated with HSP. We found that locomotor defects found in all of our spastin models could be partially rescued by phenazine, methylene blue, N-acetyl-cysteine, guanabenz and salubrinal. In addition, we show that established biomarkers of ER stress levels correlated with improved locomotor activity upon treatment across model organisms. Our results provide insights into biomarkers and novel therapeutic avenues for HSP.


Assuntos
Modelos Animais de Doenças , Paraplegia Espástica Hereditária/tratamento farmacológico , Adenosina Trifosfatases/genética , Animais , Caenorhabditis elegans , Drosophila , Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/genética , Feminino , Humanos , Locomoção/efeitos dos fármacos , Locomoção/genética , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Mutação , Fenazinas/farmacologia , Fenótipo , Paraplegia Espástica Hereditária/genética , Peixe-Zebra
10.
Hum Mol Genet ; 24(1): 86-99, 2015 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-25205109

RESUMO

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by polyglutamine expansions in the amino-terminal region of the huntingtin (Htt) protein. At the cellular level, neuronal death is accompanied by the proteolytic cleavage, misfolding and aggregation of huntingtin. Abnormal hyperphosphorylation of tau protein is a characteristic feature of a class of neurodegenerative diseases called tauopathies. As a number of studies have reported tau pathology in HD patients, we investigated whether HD pathology may promote tau hyperphosphorylation and if so tackle some of its underlying mechanisms. For that purpose, we used the R6/2 mouse, a well-characterized model of HD, and analyzed tau phosphorylation before and after the onset of HD-like symptoms. We found a significant increase in tau hyperphosphorylation at the PHF-1 epitope in pre-symptomatic R6/2 mice, whereas symptomatic mice displayed tau hyperphosphorylation at multiple tau phosphoepitopes (AT8, CP13, PT205 and PHF-1). There was no activation of major tau kinases that could explain this observation. However, when we examined tau phosphatases, we found that calcineurin/PP2B was downregulated by 30% in pre-symptomatic and 50% in symptomatic R6/2 mice, respectively. We observed similar changes in tau phosphorylation and calcineurin expression in Q175 mice, another HD model. Calcineurin was also reduced in Q111 compared with Q7 cells. Finally, pharmacological or genetic inhibition of endogenous calcineurin was sufficient to promote tau hyperphosphorylation in neuronal cells. Taken together, our data suggest that mutant huntingtin can induce abnormal tau hyperphosphorylation in vivo, via the deregulation of calcineurin.


Assuntos
Encéfalo/citologia , Calcineurina/metabolismo , Doença de Huntington/metabolismo , Neurônios/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Proteínas tau/metabolismo , Animais , Encéfalo/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Doença de Huntington/genética , Camundongos , Camundongos Transgênicos , Fosforilação
11.
PLoS Biol ; 12(6): e1001895, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24960609

RESUMO

The Wnt receptor Ryk is an evolutionary-conserved protein important during neuronal differentiation through several mechanisms, including γ-secretase cleavage and nuclear translocation of its intracellular domain (Ryk-ICD). Although the Wnt pathway may be neuroprotective, the role of Ryk in neurodegenerative disease remains unknown. We found that Ryk is up-regulated in neurons expressing mutant huntingtin (HTT) in several models of Huntington's disease (HD). Further investigation in Caenorhabditis elegans and mouse striatal cell models of HD provided a model in which the early-stage increase of Ryk promotes neuronal dysfunction by repressing the neuroprotective activity of the longevity-promoting factor FOXO through a noncanonical mechanism that implicates the Ryk-ICD fragment and its binding to the FOXO co-factor ß-catenin. The Ryk-ICD fragment suppressed neuroprotection by lin-18/Ryk loss-of-function in expanded-polyQ nematodes, repressed FOXO transcriptional activity, and abolished ß-catenin protection of mutant htt striatal cells against cell death vulnerability. Additionally, Ryk-ICD was increased in the nucleus of mutant htt cells, and reducing γ-secretase PS1 levels compensated for the cytotoxicity of full-length Ryk in these cells. These findings reveal that the Ryk-ICD pathway may impair FOXO protective activity in mutant polyglutamine neurons, suggesting that neurons are unable to efficiently maintain function and resist disease from the earliest phases of the pathogenic process in HD.


Assuntos
Fatores de Transcrição Forkhead/metabolismo , Doença de Huntington/etiologia , Neurônios/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptores Wnt/metabolismo , Idoso , Animais , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Linhagem Celular , Feminino , Humanos , Doença de Huntington/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Presenilina-1/metabolismo , Receptores Proteína Tirosina Quinases/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Via de Sinalização Wnt
12.
PLoS Genet ; 10(5): e1004346, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24785260

RESUMO

Glucose is a major energy source and is a key regulator of metabolism but excessive dietary glucose is linked to several disorders including type 2 diabetes, obesity and cardiac dysfunction. Dietary intake greatly influences organismal survival but whether the effects of nutritional status are transmitted to the offspring is an unresolved question. Here we show that exposing Caenorhabditis elegans to high glucose concentrations in the parental generation leads to opposing negative effects on fecundity, while having protective effects against cellular stress in the descendent progeny. The transgenerational inheritance of glucose-mediated phenotypes is dependent on the insulin/IGF-like signalling pathway and components of the histone H3 lysine 4 trimethylase complex are essential for transmission of inherited phenotypes. Thus dietary over-consumption phenotypes are heritable with profound effects on the health and survival of descendants.


Assuntos
Caenorhabditis elegans/metabolismo , Glucose/metabolismo , Estresse Fisiológico , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiologia , Células Germinativas , Estresse Oxidativo
14.
J Neurosci ; 34(36): 12093-103, 2014 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-25186754

RESUMO

Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease with either sporadic or genetic origins characterized by the progressive degeneration of motor neurons. At the cellular level, ALS neurons show protein misfolding and aggregation phenotypes. Transactive response DNA-binding protein 43 (TDP-43) has recently been shown to be associated with ALS, but the early pathophysiological deficits causing impairment in motor function are unknown. Here we used Caenorhabditis elegans expressing mutant TDP-43(A315T) in motor neurons and explored the potential influences of calcium (Ca(2+)). Using chemical and genetic approaches to manipulate the release of endoplasmic reticulum (ER) Ca(2+)stores, we observed that the reduction of intracellular Ca(2+) ([Ca(2+)]i) rescued age-dependent paralysis and prevented the neurodegeneration of GABAergic motor neurons. Our data implicate elevated [Ca(2+)]i as a driver of TDP-43-mediated neuronal toxicity. Furthermore, we discovered that neuronal degeneration is independent of the executioner caspase CED-3, but instead requires the activity of the Ca(2+)-regulated calpain protease TRA-3, and the aspartyl protease ASP-4. Finally, chemically blocking protease activity protected against mutant TDP-43(A315T)-associated neuronal toxicity. This work both underscores the potential of the C. elegans system to identify key targets for therapeutic intervention and suggests that a focused effort to regulate ER Ca(2+) release and necrosis-like degeneration consequent to neuronal injury may be of clinical importance.


Assuntos
Envelhecimento/metabolismo , Caenorhabditis elegans/fisiologia , Sinalização do Cálcio , Proteínas de Ligação a DNA/metabolismo , Neurônios GABAérgicos/metabolismo , Neurônios Motores/metabolismo , Envelhecimento/fisiologia , Animais , Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/antagonistas & inibidores , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Cálcio/metabolismo , Calpaína/antagonistas & inibidores , Calpaína/genética , Calpaína/metabolismo , Caspases/genética , Caspases/metabolismo , Proteínas de Ligação a DNA/genética , Retículo Endoplasmático/metabolismo , Neurônios GABAérgicos/patologia , Neurônios GABAérgicos/fisiologia , Locomoção , Neurônios Motores/patologia , Neurônios Motores/fisiologia , Necrose , Paralisia/genética , Paralisia/metabolismo , Inibidores de Proteases/farmacologia
15.
Hum Mol Genet ; 22(4): 782-94, 2013 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-23172908

RESUMO

The DNA/RNA binding proteins TAR DNA-binding protein 43 (TDP-43) and fused-in-sarcoma (FUS) are genetically linked to amyotrophic lateral sclerosis and frontotemporal lobar dementia, while the inappropriate cytoplasmic accumulations of TDP-43 and FUS are observed in a growing number of late-onset pathologies including spinocerebellar ataxia 3, Alzheimer's and Huntington's diseases (HD). To investigate if TDP-43 and FUS contribute to neurodegenerative phenotypes, we turned to a genetically accessible Caenorhabditis elegans model of polyglutamine toxicity. In C. elegans, we observe that genetic loss-of-function mutations for nematode orthologs of TDP-43 or FUS reduced behavioral defects and neurodegeneration caused by huntingtin exon-1 with expanded polyglutamines. Furthermore, using striatal cells from huntingtin knock-in mice we observed that small interfering ribonucleic acid (siRNA) against TDP-43 or FUS reduced cell death caused by mutant huntingtin. Moreover, we found that TDP-43 and the survival factor progranulin (PGRN) genetically interact to regulate polyglutamine toxicity in C. elegans and mammalian cells. Altogether our data point towards a conserved function for TDP-43 and FUS in promoting polyglutamine toxicity and that delivery of PGRN may have therapeutic benefits.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Ligação a DNA/metabolismo , Doença de Huntington/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/metabolismo , Peptídeos/metabolismo , Animais , Animais Geneticamente Modificados , Axônios/patologia , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/genética , Linhagem Celular , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Granulinas , Histona Desacetilases/metabolismo , Humanos , Proteína Huntingtina , Doença de Huntington/patologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Camundongos , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Peptídeos/genética , Progranulinas , RNA Interferente Pequeno/genética
16.
PLoS Genet ; 8(7): e1002806, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22792076

RESUMO

TDP-43 is a multifunctional nucleic acid binding protein linked to several neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia. To learn more about the normal biological and abnormal pathological role of this protein, we turned to Caenorhabditis elegans and its orthologue TDP-1. We report that TDP-1 functions in the Insulin/IGF pathway to regulate longevity and the oxidative stress response downstream from the forkhead transcription factor DAF-16/FOXO3a. However, although tdp-1 mutants are stress-sensitive, chronic upregulation of tdp-1 expression is toxic and decreases lifespan. ALS-associated mutations in TDP-43 or the related RNA binding protein FUS activate the unfolded protein response and generate oxidative stress leading to the daf-16-dependent upregulation of tdp-1 expression with negative effects on neuronal function and lifespan. Consistently, deletion of endogenous tdp-1 rescues mutant TDP-43 and FUS proteotoxicity in C. elegans. These results suggest that chronic induction of wild-type TDP-1/TDP-43 by cellular stress may propagate neurodegeneration and decrease lifespan.


Assuntos
Caenorhabditis elegans/genética , Proteínas de Ligação a DNA/genética , Longevidade/genética , Neurônios , Estresse Oxidativo , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição Forkhead , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Regulação da Expressão Gênica , Proteínas de Choque Térmico/metabolismo , Humanos , Insulina/genética , Insulina/metabolismo , Longevidade/fisiologia , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo/genética , Transdução de Sinais , Somatomedinas/genética , Somatomedinas/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
18.
Nat Genet ; 37(4): 349-50, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15793589

RESUMO

We report that Sir2 activation through increased sir-2.1 dosage or treatment with the sirtuin activator resveratrol specifically rescued early neuronal dysfunction phenotypes induced by mutant polyglutamines in transgenic Caenorhabditis elegans. These effects are dependent on daf-16 (Forkhead). Additionally, resveratrol rescued mutant polyglutamine-specific cell death in neuronal cells derived from HdhQ111 knock-in mice. We conclude that Sir2 activation may protect against mutant polyglutamines.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Glicoproteínas de Membrana/fisiologia , Proteínas de Membrana Transportadoras/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Neurônios/fisiologia , Peptídeos/toxicidade , Sirtuínas/metabolismo , Estilbenos/farmacologia , Fatores de Transcrição/metabolismo , Inibidores da Angiogênese/farmacologia , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Fatores de Transcrição Forkhead , Homozigoto , Glicoproteínas de Membrana/genética , Proteínas de Membrana Transportadoras/genética , Camundongos , Camundongos Mutantes , Proteínas do Tecido Nervoso/genética , Neurônios/citologia , Resveratrol , Proteínas da Membrana Plasmática de Transporte de Serotonina , Sirtuínas/genética , Fatores de Transcrição/genética
19.
J Alzheimers Dis ; 101(1): 49-60, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39093068

RESUMO

Background: Recent advances linking gut dysbiosis with neurocognitive disorders such as Alzheimer's disease (AD) suggest that the microbiota-gut-brain axis could be targeted for AD prevention, management, or treatment. Objective: We sought to identify probiotics that can delay Aß-induced paralysis. Methods: Using C. elegans expressing human amyloid-ß (Aß)1-42 in body wall muscles (GMC101), we assessed the effects of several probiotic strains on paralysis. Results: We found that Lacticaseibacillus rhamnosus HA-114 and Bacillus subtilis R0179, but not their supernatants or heat-treated forms, delayed paralysis and prolonged lifespan without affecting the levels of amyloid-ß aggregates. To uncover the mechanism involved, we explored the role of two known pathways involved in neurogenerative diseases, namely mitophagy, via deletion of the mitophagy factor PINK-1, and fatty acid desaturation, via deletion of the Δ9 desaturase FAT-5. Pink-1 deletion in GMC101 worms did not modify the life-prolonging and anti-paralysis effects of HA-114 but reduced the protective effect of R0179 against paralysis without affecting its life-prolonging effect. Upon fat5 deletion in GMC101 worms, the monounsaturated C14:1 and C16:1 FAs conserved their beneficial effect while the saturated C14:0 and C16:0 FAs did not. The beneficial effects of R0179 on both lifespan and paralysis remained unaffected by fat-5 deletion, while the beneficial effect of HA-114 on paralysis and lifespan was significantly reduced. Conclusions: Collectively with clinical and preclinical evidence in other models, our results suggest that HA-114 or R0179 could be studied as potential therapeutical adjuncts in neurodegenerative diseases such as AD.


Assuntos
Peptídeos beta-Amiloides , Bacillus subtilis , Caenorhabditis elegans , Lacticaseibacillus rhamnosus , Longevidade , Probióticos , Animais , Longevidade/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/toxicidade , Paralisia , Fragmentos de Peptídeos/toxicidade , Fragmentos de Peptídeos/metabolismo , Animais Geneticamente Modificados , Humanos , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo
20.
Microorganisms ; 12(4)2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38674579

RESUMO

The bidirectional relationship between the gut microbiota and the nervous system is known as the microbiota-gut-brain axis (MGBA). The MGBA controls the complex interactions between the brain, the enteric nervous system, the gut-associated immune system, and the enteric neuroendocrine systems, regulating key physiological functions such as the immune response, sleep, emotions and mood, food intake, and intestinal functions. Psychobiotics are considered tools with the potential to modulate the MGBA through preventive, adjunctive, or curative approaches, but their specific mechanisms of action on many aspects of health are yet to be characterized. This narrative review and perspectives article highlights the key paradigms needing attention as the scope of potential probiotics applications in human health increases, with a growing body of evidence supporting their systemic beneficial effects. However, there are many limitations to overcome before establishing the extent to which we can incorporate probiotics in the management of neuropsychiatric disorders. Although this article uses the term probiotics in a general manner, it remains important to study probiotics at the strain level in most cases.

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