Intracellular amyloid formation in muscle cells of Aβ-transgenic Caenorhabditis elegans: determinants and physiological role in copper detoxification

Minniti, Alicia N.; Rebolledo, Daniela L.; Grez, Paula M.; Fadić, Ricardo; Aldunate, Rebeca; Volitakis, Irene; Cherny, Robert A.; Opazo, Carlos; Masters, Colin L.; Bush, Ashley I.; Inestrosa, Nibaldo C.

doi:10.1186/1750-1326-4-2

Cited by 41 publications

(42 citation statements)

References 72 publications

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“…We previously reported that copper treatment increases the number and size of amyloid deposits in this model (Minniti et al, 2009). At the time, we also showed some data that hinted at the possibility of copper being able to ameliorate the motility impairments in A␤ transgenic C. elegans.…”

Section: Copper Treatment Improves Synaptic Function In A␤ Transgenicsupporting

confidence: 64%

“…Transgenic C. elegans expressing A␤ show synaptic defects Under normal culture conditions, we previously observed that adult worms expressing A␤ constitutively move significantly slower than the controls that do not express A␤ (Minniti et al, 2009). We hypothesized that the compromised motility of A␤ transgenic worms in liquid medium could be, at least in part, the result of A␤-induced defects at the neuromuscular junction (NMJ), leading to synaptic transmission failure and decreased motor capacity.…”

Section: Resultsmentioning

confidence: 99%

“…Three independent experimentswereperformedintriplicate.ComparingA␤transgenicwormswiththecontrolsthatdonotexpressA␤:**pϭ0.01,***pϭ 0.001. Comparing the untreated with the copper treated A␤ transgenic strain: posits (Minniti et al, 2009), improvement of motility, and recovery of a normal response to nicotine. In the temperatureinducible strain, copper treatment delays A␤-induced paralysis.…”

Section: Copper Treatment Decreases the Relative Amounts Of Soluble Amentioning

confidence: 99%

“…When A␤ is expressed in muscle cells, pathological behaviors include paralysis in A␤ thermo-inducible strains (Link et al, 2003) and slow movement in liquid medium in constitutive A␤ strains (Minniti et al, 2009). Serotonin hypersensitivity, altered chemotaxis, and learning deficits have been reported when A␤ is expressed in neurons (Wu et al, 2006;Dosanjh et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Copper Reduces A Oligomeric Species and Ameliorates Neuromuscular Synaptic Defects in a C. elegans Model of Inclusion Body Myositis

Rebolledo¹,

Aldunate²,

Kohn³

et al. 2011

Journal of Neuroscience

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Alzheimer's disease and inclusion body myositis (IBM) are disorders frequently found in the elderly and characterized by the presence of amyloid-␤ peptide (A␤) aggregates. We used Caenorhabditis elegans that express A␤ in muscle cells as a model of IBM, with the aim of analyzing A␤-induced muscle pathology and evaluating the consequences of modulating A␤ aggregation.First, we tested whether the altered motility we observed in the A␤ transgenic strain could be the result of a compromised neuromuscular synapse. Our pharmacological analyses show that synaptic transmission is defective in our model and suggest a specific defect on nicotine-sensitive acetylcholine receptors (AChRs). Through GFP-coupled protein visualization, we found that synaptic dysfunction correlates with mislocalization of ACR-16, the AChR subunit essential for nicotine-triggered currents.Histological and biochemical analysis allowed us to determine that copper treatment increases the amyloid deposits and decreases A␤ oligomers in this model. Furthermore, copper treatment improves motility, ACR-16 localization, and synaptic function and delays A␤-induced paralysis. Our results indicate that copper modulates A␤-induced pathology and suggest that A␤ oligomers are triggering neuromuscular dysfunction. Our findings emphasize the importance of neuromuscular synaptic dysfunction and the relevance of modulating the amyloidogenic component as an alternative therapeutic approach for this debilitating disease.

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Section: Copper Treatment Improves Synaptic Function In A␤ Transgenicsupporting

confidence: 64%

Section: Resultsmentioning

confidence: 99%

Section: Copper Treatment Decreases the Relative Amounts Of Soluble Amentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Copper Reduces A Oligomeric Species and Ameliorates Neuromuscular Synaptic Defects in a C. elegans Model of Inclusion Body Myositis

Rebolledo¹,

Aldunate²,

Kohn³

et al. 2011

Journal of Neuroscience

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“…These deposits co-localise with amyloid-specific dyes, and display a fibrillar ultrastructure [147,148]. This model (strain CL2006) was used to show that specific point mutations in Aβ can affect the formation of the amyloid deposits [147,149], that Aβ interacts with and induces the expression of the HSP-16 family of heat-shock proteins [150,151], and that daf-2(RNAi) and dietary restriction can both reduce Aβ toxicity [152,153].…”

Section: Inclusion Body Myositismentioning

confidence: 99%

C. elegans models of neuromuscular diseases expedite translational research

Sleigh

Sattelle²

2010

Translational Neuroscience

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The nematode Caenorhabditis elegans is a genetic model organism and the only animal with a complete nervous system wiring diagram. With only 302 neurons and 95 striated muscle cells, a rich array of mutants with defective locomotion and the facility for individual targeted gene knockdown by RNA interference, it lends itself to the exploration of gene function at nerve muscle junctions. With approximately 60% of human disease genes having a C. elegans homologue, there is growing interest in the deployment of lowcost, high-throughput, drug screens of nematode transgenic and mutant strains mimicking aspects of the pathology of devastating human neuromuscular disorders. Here we explore the contributions already made by C. elegans to our understanding of muscular dystrophies (Duchenne and Becker), spinal muscular atrophy, amyotrophic lateral sclerosis, Friedreich’s ataxia, inclusion body myositis and the prospects for contributions to other neuromuscular disorders. A bottleneck to low-cost, in vivo, large-scale chemical library screening for new candidate therapies has been rapid, automated, behavioural phenotyping. Recent progress in quantifying simple swimming (thrashing) movements is making such screening possible and is expediting the translation of drug candidates towards the clinic.

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Inhibition of amyloid‐induced toxicity by ergothioneine in a transgenic Caenorhabditis elegans model

Cheah

et al. 2019

FEBS Letters

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The abnormal accumulation of β‐amyloid peptide (Aβ) is recognized as a central component in the pathogenesis of Alzheimer disease. While many aspects of Aβ‐mediated neurotoxicity remain elusive, Aβ has been associated with numerous underlying pathologies, including oxidative and nitrosative stress, inflammation, metal ion imbalance, mitochondrial dysfunction, and even tau pathology. Ergothioneine (ET), a naturally occurring thiol/thione‐derivative of histidine, has demonstrated antioxidant and neuroprotective properties against various oxidative and neurotoxic stressors. This study investigates ET’s potential to counteract Aβ‐toxicity in transgenic Caenorhabditis elegans overexpressing a human Aβ peptide. The accumulation of Aβ in this model leads to paralysis and premature death. We show that ET dose‐dependently reduces Aβ‐oligomerization and extends the lifespan and healthspan of the nematodes.

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Intracellular amyloid formation in muscle cells of Aβ-transgenic Caenorhabditis elegans: determinants and physiological role in copper detoxification

Cited by 41 publications

References 72 publications

Copper Reduces A Oligomeric Species and Ameliorates Neuromuscular Synaptic Defects in a C. elegans Model of Inclusion Body Myositis

Copper Reduces A Oligomeric Species and Ameliorates Neuromuscular Synaptic Defects in a C. elegans Model of Inclusion Body Myositis

C. elegans models of neuromuscular diseases expedite translational research

Inhibition of amyloid‐induced toxicity by ergothioneine in a transgenic Caenorhabditis elegans model

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