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

Rebolledo, Daniela L.; Aldunate, Rebeca; Kohn, Rebecca; Neira, Iván; Minniti, Alicia N.; Inestrosa, Nibaldo C.

doi:10.1523/jneurosci.0336-11.2011

Cited by 41 publications

(34 citation statements)

References 73 publications

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“…In our study, glucose gradually induced Aβ oligomerization accompanied by decrease in Aβ monomers. These results are in agreement with previous studies where carbohydrate-rich diets accelerated the neurodegeneration by increasing Aβ oligomers [467,468], and reduction in Aβ oligomerization resulted in improved disease pathology [57,411,515]. In our study, we also found that administration of 2DOG reduced disease pathology by decreasing Aβ oligomerization.…”

Section: Discussionsupporting

confidence: 93%

“…ACh neurotransmission is essential for muscle contraction, but increased ACh levels can result in paralysis due to muscle overexcitation. As a result, Aβ expression can provide resistance to cholinergic agonists such as aldicarb, that increases synaptic levels of ACh, or levamisole, that increases ACh receptor sensitization [411,529]. Aldicarb resistance is used as an indication of pre-synaptic defects whereas resistance against both aldicarb and levamisole is used as an indication of post-synaptic defects [417].…”

Section: Discussionmentioning

confidence: 99%

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Metabolic study of Alzheimer’s disease using mutant C. elegans

Ahmad¹

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Alzheimer's disease (AD) is associated with chronic neurodegeneration and is the cause of the most common form of dementia. The main hallmarks of AD are aggregates of amyloid beta (Aβ) and formation of hyperphosphorylated tau neurofibrillary tangles (NFTs). Unfortunately, after more than 100 years of research the exact cause(s) and mechanisms involved in AD progression remain unclarified. Evidence indicates that impaired mitochondrial bioenergetics may precede by decades, the neurodegeneration and cognitive decline associated with AD. Moreover, a genetic association of the core metabolic enzyme dihydrolipoamide dehydrogenase (DLD) with late-onset AD and reduced activity of DLD-containing enzymes suggests glucose hypo-metabolism as a possible cause of AD. Contrary to this, improvements of AD symptoms under caloric restriction or other means of reducing-glucose dependent energy metabolism supports an alternative hypothesis that a decrease in glucose metabolism may be protective. In the present study, we used mutant Caenorhabditis elegans (C. elegans) to investigate the effect of glucose metabolism on AD progression. We initially looked at the role of suppressed DLD-1, and then we focused on the effect of high glucose in AD pathogenesis.Transgenic expression of Aβ in C. elegans causes both phenotypic and behavioral defects and results in accumulation of toxic Aβ oligomers, culminating in protein aggregation as is normally associated with AD pathophysiology. Aβ expression in worm muscle causes agedependent progressive paralysis and impaired acetylcholine neurotransmission while neuronal Aβ expression results in defective chemotaxis and impaired serotonin sensitivity as well as reduced fecundity and egg hatching. Suppression of the dld-1 gene alleviated paralysis, improved acetylcholine neurotransmission, enhanced chemotaxis and restored normal sensitivity to serotonin.dld-1 gene suppression also protects vitality as indicated by improved fecundity and egg hatching.Interestingly, protective effects of dld-1 suppression could be reversed using the calcium ionophore (CaI), indicating that the protective mechanism involves calcium signaling. Each of these beneficial effects of dld-1 gene suppression could be mimicked using a specific, small molecule inhibitor of the DLD-1 enzyme, 5-methoxyindole-2-carboxylic acid (MICA).High glucose levels are associated with the metabolic disorder, diabetes, which is a major risk factor for AD. In fact, it has been suggested that AD is a neural form of diabetes, type 3 diabetes. If true, drugs used to treat diabetes could act as possible treatments for AD. In this study, I investigated the effect of elevated glucose, the glucose metabolism inhibitor, 2-deoxy-d-glucose ii (2DOG) as well as the anti-diabetes drugs, metformin and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), on AD progression. Elevated glucose in the growth medium induced hyperactivity, which interfered with the paralysis assays, but it was seen to impair cholinergic neurotransmission, egg laying and hatc...

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Metabolic study of Alzheimer’s disease using mutant C. elegans

Ahmad¹

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“…The deletion of the msra-1 gene heightens the locomotory impairments of Ab transgenic worms Muscle expression of Ab causes locomotory impairments in C. elegans (40,56). To test the relevance of oxidation repair in this model of IBM, we first evaluated locomotion in a transgenic strain that carries a deletion of the msra-1 gene (allele tm1421) and expresses the human Ab peptide in muscle cells.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, Ab seems to specifically affect the subtype of nicotinic acetylcholine receptors that are sensitive to nicotine but insensitive to levamisole (40,56). These receptors are closely related to the a7-nicotinic acetylcholine receptor, proposed to be associated with Ab 1-42 neurotoxic effects in mammals (55,59).…”

Section: Resultsmentioning

confidence: 99%

“…Ab oligomers are also present in muscle biopsies from IBM patients (52). We previously showed that, in a Caenorhabditis elegans model of IBM, there are structural defects in the NMJ as well as synaptic dysfunction, and that Ab oligomeric species are the main toxic forms of the peptide (56). This IBM model expresses the human Ab peptide in muscle cells and has been extensively used to elucidate the molecular mechanisms of AD and IBM (32,57,59).…”

Section: Innovationmentioning

confidence: 99%

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The Protein Oxidation Repair Enzyme Methionine Sulfoxide Reductase A Modulates Aβ Aggregation and ToxicityIn Vivo

Minniti

Arrázola

Bravo‐Zehnder

et al. 2015

Antioxidants & Redox Signaling

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Aims: To examine the role of the enzyme methionine sulfoxide reductase A-1 (MSRA-1) in amyloid-b peptide (Ab)-peptide aggregation and toxicity in vivo, using a Caenorhabditis elegans model of the human amyloidogenic disease inclusion body myositis. Results: MSRA-1 specifically reduces oxidized methionines in proteins. Therefore, a deletion of the msra-1 gene was introduced into transgenic C. elegans worms that express the Ab-peptide in muscle cells to prevent the reduction of oxidized methionines in proteins. In a constitutive transgenic Ab strain that lacks MSRA-1, the number of amyloid aggregates decreases while the number of oligomeric Ab species increases. These results correlate with enhanced synaptic dysfunction and mislocalization of the nicotinic acetylcholine receptor ACR-16 at the neuromuscular junction (NMJ). Innovation: This approach aims at modulating the oxidation of Ab in vivo indirectly by dismantling the methionine sulfoxide repair system. The evidence presented here shows that the absence of MSRA-1 influences Ab aggregation and aggravates locomotor behavior and NMJ dysfunction. The results suggest that therapies which boost the activity of the Msr system could have a beneficial effect in managing amyloidogenic pathologies. Conclusion: The absence of MSRA-1 modulates Ab-peptide aggregation and increments its deleterious effects in vivo. Antioxid. Redox Signal. 22,[48][49][50][51][52][53][54][55][56][57][58][59][60][61][62]

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Glutamate protects neuromuscular junctions from deleterious effects of β-amyloid peptide and conversely: An in vitro study in a nerve-muscle coculture

Combes¹,

Poindron²,

Callizot³

2014

Journal of Neuroscience Research

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Murine models of Alzheimer's disease with elevated levels of amyloid-β (Aβ) peptide present motor axon defects and neuronal death. Aβ1-42 accumulation is observed in motor neurons and spinal cords of sporadic and familial cases of amyotrophic lateral sclerosis (ALS). Motor neurons are highly susceptible to glutamate, which has a role in ALS neuronal degeneration. The current study investigates the link between Aβ and glutamate in this neurodegenerative process. Primary rat nerve and human muscle cocultures were intoxicated with glutamate or Aβ. Neuromuscular junction (NMJ) mean size and neurite length were evaluated. The role of N-methyl-D-aspartate receptor (NMDAR) was investigated by using MK801. Glutamate and Aβ production were evaluated in culture supernatant. The current study shows that NMJs are highly sensitive to Aβ peptide, that the toxic pathway involves glutamate and NMDAR, and that glutamate and Aβ act in an interlinked manner. Some motor diseases (e.g., ALS), therefore, could be considered from a new point of view related to these balance disturbances.

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

Cited by 41 publications

References 73 publications

Metabolic study of Alzheimer’s disease using mutant C. elegans

Metabolic study of Alzheimer’s disease using mutant C. elegans

The Protein Oxidation Repair Enzyme Methionine Sulfoxide Reductase A Modulates Aβ Aggregation and ToxicityIn Vivo

Glutamate protects neuromuscular junctions from deleterious effects of β-amyloid peptide and conversely: An in vitro study in a nerve-muscle coculture

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