Polyglutamine Proteins at the Pathogenic Threshold Display Neuron-Specific Aggregation in a Pan-Neuronal<i>Caenorhabditis elegans</i>Model

Brignull, Heather R.; Moore, Finola; Tang, Stephanie; Morimoto, Richard I.

doi:10.1523/jneurosci.0990-06.2006

Cited by 192 publications

(232 citation statements)

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“…Whether this form of pathological behavior uses molecular mechanisms common to higher animals remains to be determined. A similar approach has recently revealed polyglutamine threshold toxicity in a transgenic C. elegans model of Huntington's disease (Brignull et al, 2006). (Fig.…”

Section: Discussionmentioning

confidence: 89%

Amyloid-β-Induced Pathological Behaviors Are Suppressed byGinkgo bilobaExtract EGb 761 and Ginkgolides in TransgenicCaenorhabditis elegans

Wu¹,

Wu²,

Butko³

et al. 2006

J. Neurosci.

371

366

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Amyloid-␤ (A␤) toxicity has been postulated to initiate synaptic loss and subsequent neuronal degeneration seen in Alzheimer's disease (AD). We previously demonstrated that the standardized Ginkgo biloba extract EGb 761, commonly used to enhance memory and by AD patients for dementia, inhibits A␤-induced apoptosis in neuroblastoma cells. In this study, we use EGb 761 and its single constituents to associate A␤ species with A␤-induced pathological behaviors in a model organism, Caenorhabditis elegans. We report that EGb 761 and one of its components, ginkgolide A, alleviates A␤-induced pathological behaviors, including paralysis, and reduces chemotaxis behavior and 5-HT hypersensitivity in a transgenic C. elegans. We also show that EGb 761 inhibits A␤ oligomerization and A␤ deposits in the worms. Moreover, reducing oxidative stress is not the mechanism by which EGb 761 and ginkgolide A suppress A␤-induced paralysis because the antioxidant L-ascorbic acid reduced intracellular levels of hydrogen peroxide to the same extent as EGb 761, but was not nearly as effective in suppressing paralysis in the transgenic C. elegans. These findings suggest that (1) EGb 761 suppresses A␤-related pathological behaviors, (2) the protection against A␤ toxicity by EGb 761 is mediated primarily by modulating A␤ oligomeric species, and (3) ginkgolide A has therapeutic potential for prevention and treatment of AD.

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Section: Discussionmentioning

confidence: 89%

Amyloid-β-Induced Pathological Behaviors Are Suppressed byGinkgo bilobaExtract EGb 761 and Ginkgolides in TransgenicCaenorhabditis elegans

Wu¹,

Wu²,

Butko³

et al. 2006

J. Neurosci.

371

366

View full text Add to dashboard Cite

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“…These advantages, together with genome-wide tools for genetic screens and a short life cycle and life span, also allow rapid testing of hypotheses. Observations from many laboratories have shown that polyQ or A␤ proteins are toxic in multiple cells and tissues of Drosophila and C. elegans including retinal neurons, chemosensory, mechanosensory, motor neurons, and body wall muscle cells (Link 1995;Warrick et al 1998;Faber et al 1999;Marsh et al 2000;Parker et al 2001;Morley et al 2002;Takeyama et al 2002;Brignull et al 2006). While no single model recapitulates all features of a disease it is evident that each system has contributed unique insights that have validated the general approach.…”

Section: Insights On Neurodegenerative Disease and Protein Conformatimentioning

confidence: 99%

Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging

Morimoto¹

2008

Genes Dev.

808

767

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The long-term health of the cell is inextricably linked to protein quality control. Under optimal conditions this is accomplished by protein homeostasis, a highly complex network of molecular interactions that balances protein biosynthesis, folding, translocation, assembly/disassembly, and clearance. This review will examine the consequences of an imbalance in homeostasis on the flux of misfolded proteins that, if unattended, can result in severe molecular damage to the cell. Adaptation and survival requires the ability to sense damaged proteins and to coordinate the activities of protective stress response pathways and chaperone networks. Yet, despite the abundance and apparent capacity of chaperones and other components of homeostasis to restore folding equilibrium, the cell appears poorly adapted for chronic proteotoxic stress when conformationally challenged aggregation-prone proteins are expressed in cancer, metabolic disease, and neurodegenerative disease. The decline in biosynthetic and repair activities that compromises the integrity of the proteome is influenced strongly by genes that control aging, thus linking stress and protein homeostasis with the health and life span of the organism.Protein homeostasis is the cellular process that governs the "life of proteins." More than protein quality control alone, protein homeostasis encompasses RNA metabolism and processing, protein synthesis, folding, translocation, assembly/disassembly, and clearance (Balch et al. 2008). These processes and their roles in protein homeostasis can be viewed as a systems network in which each process, or hub, is organized as mininetworks interconnected to other hubs. An implicit assumption of protein homeostasis is that each hub should be dynamic, and therefore have sufficient "buffering" capacity to respond to various imbalances in network components and flux of misfolded species and damaged proteins. Tissue-specific differences in expression of components of the homeostasis network such as chaperones and components of the proteasome, autophagy, or transport machinery could be a basis for the sensitivity of neuronal cells during aging and disease.Two prominent modulators of protein homeostasis are molecular chaperones and stress-inducible responses. Chaperones are abundantly expressed in multiple compartments of the cell and are thought to comprise a significant fraction of the cellular machinery (Bukau et al. 2006;Ron and Walter 2007). Only limited information is available on the concentration of chaperones in a eukaryotic cell and the fraction that is functionally engaged with substrates or freely available in reserve. Nevertheless, this has led to a commonly held expectation that within the cell, chaperones have excess folding capacity and can exist in a free state to buffer unexpected folding requirements. This would require the cell to maintain a stockpile of chaperones for protein folding emergencies. A counter view is that the cell has little excess chaperone capacity, and that the concentration of chaperones is titrat...

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“…Worms were imaged using an Axioimager (Zeiss) or an Ultraview Vox spinning disc confocal (Perkin Elmer) microscope and analyzed with either Axiovision 4.7 (Zeiss) or Volocity 5 (Perkin Elmer) software. Fluorescence recovery after photobleaching (FRAP) analysis was performed as previously described (Brignull et al 2006).…”

Section: Rnaimentioning

confidence: 99%

“…This might be due to the lower copy number of our SRP-2 transgenes, which were integrated by biolistic transformation avoiding excessive overexpression (Praitis et al 2001). To further define the nature of SRP-2 aggregates, we performed FRAP experiments for SRP-2 H302R , YFP, and polyQ-YFP expressed in body wall muscle cells (Morley et al 2002;Brignull et al 2006). In contrast to the wild-type protein, no obvious recovery was detectable for the mutant form ( Figure 3, B and C), indicating that SRP-2 H302R forms insoluble polymers within cellular compartments.…”

Section: Analysis Of Srp-2 Aggregation In C Elegansmentioning

confidence: 99%

A Novel Interaction Between Aging and ER Overload in a Protein Conformational Dementia

et al. 2013

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Intraneuronal deposition of aggregated proteins in tauopathies, Parkinson disease, or familial encephalopathy with neuroserpin inclusion bodies (FENIB) leads to impaired protein homeostasis (proteostasis). FENIB represents a conformational dementia, caused by intraneuronal polymerization of mutant variants of the serine protease inhibitor neuroserpin. In contrast to the aggregation process, the kinetic relationship between neuronal proteostasis and aggregation are poorly understood. To address aggregate formation dynamics, we studied FENIB in Caenorhabditis elegans and mice. Point mutations causing FENIB also result in aggregation of the neuroserpin homolog SRP-2 most likely within the ER lumen in worms, recapitulating morphological and biochemical features of the human disease. Intriguingly, we identified conserved protein quality control pathways to modulate protein aggregation both in worms and mice. Specifically, downregulation of the unfolded protein response (UPR) pathways in the worm favors mutant SRP-2 accumulation, while mice overexpressing a polymerizing mutant of neuroserpin undergo transient induction of the UPR in young but not in aged mice. Thus, we find that perturbations of proteostasis through impairment of the heat shock response or altered UPR signaling enhance neuroserpin accumulation in vivo. Moreover, accumulation of neuroserpin polymers in mice is associated with an age-related induction of the UPR suggesting a novel interaction between aging and ER overload. These data suggest that targets aimed at increasing UPR capacity in neurons are valuable tools for therapeutic intervention.

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Polyglutamine Proteins at the Pathogenic Threshold Display Neuron-Specific Aggregation in a Pan-NeuronalCaenorhabditis elegansModel

Cited by 192 publications

References 50 publications

Amyloid-β-Induced Pathological Behaviors Are Suppressed byGinkgo bilobaExtract EGb 761 and Ginkgolides in TransgenicCaenorhabditis elegans

Amyloid-β-Induced Pathological Behaviors Are Suppressed byGinkgo bilobaExtract EGb 761 and Ginkgolides in TransgenicCaenorhabditis elegans

Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging

A Novel Interaction Between Aging and ER Overload in a Protein Conformational Dementia

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