Changes in protein turnover after heat shock are related to accumulation of abnormal proteins in aging Drosophila melanogaster

Niedzwiecki, Aleksandra; Fleming, James E.

doi:10.1016/0047-6374(90)90133-z

Cited by 16 publications

(6 citation statements)

References 38 publications

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“…Importantly, when Aβ42 mRNA levels were equalised at different ages of induction, Aβ42 peptide accumulated to higher levels in older-induced flies, and subsequently shortened lifespan only when induced at later time-points. This difference correlated with an alteration in protein turnover with age [24]. Measurement of 35 S-Methionine incorporation showed that general protein translation was reduced in older flies, consistent with published studies showing that the rate of protein synthesis decreases with age in a wide variety of cells, tissues, organs and organisms, including humans (reviewed in [25]).…”

Section: Discussionsupporting

confidence: 84%

“…Protein turnover declines with age in several organisms 24,25, suggesting that age-dependent effects on protein synthesis or degradation could explain the accumulation of Aβ42 peptide in older flies. As a measure of the rate of translation, 35 S-methionine incorporation was assessed in day-2 (RU 50 [2–9d]) and day-20 (RU 200 [20–27d]) UAS-Arc Aβ42; elavGS flies pulsed with RU486 for 1 week.…”

Section: Resultsmentioning

confidence: 99%

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Ageing Increases Vulnerability to Aβ42 Toxicity in Drosophila

et al. 2012

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Age is the major risk factor for many neurodegenerative diseases, including Alzheimer's Disease (AD), for reasons that are not clear. The association could indicate that the duration or degree of exposure to toxic proteins is important for pathology, or that age itself increases susceptibility to protein toxicity. Using an inducible Drosophila model of AD, we investigated these possibilities by varying the expression of an Aβ42 transgene in neurons at different adult ages and measuring the effects on Aβ42 levels and associated pathological phenotypes. Acute induction of Arctic Aβ42 in young adult flies resulted in rapid expression and clearance of mRNA and soluble Arctic Aβ42 protein, but in irreversible expression of insoluble Arctic Aβ42 peptide. Arctic Aβ42 peptide levels accumulated with longer durations of induction, and this led to a dose-dependent reduction in negative geotaxis and lifespan. For a standardised level of mRNA expression, older flies had higher levels of Arctic Aβ42 peptide and associated toxicity, and this correlated with an age-dependent reduction in proteasome activity. Equalising Aβ42 protein at different ages shortened lifespan in correlation with the duration of exposure to the peptide, suggesting that Aβ42 expression accumulates damage over time. However, the relative reduction in lifespan compared to controls was greater in flies first exposed to the peptide at older ages, suggesting that ageing itself also increases susceptibility to Aβ42 toxicity. Indeed older flies were more vulnerable to chronic Aβ42 toxicity even with a much lower lifetime exposure to the peptide. Finally, the persistence of insoluble Aβ42 in both young and old induced flies suggests that aggregated forms of the peptide cause toxicity in later life. Our results suggest that reduced protein turnover, increased duration of exposure and increased vulnerability to protein toxicity at later ages in combination could explain the late age-of-onset of neurodegenerative phenotypes.

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Section: Discussionsupporting

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Ageing Increases Vulnerability to Aβ42 Toxicity in Drosophila

et al. 2012

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“…Importantly, when Ab42 mRNA levels were equalised at different ages of induction, Ab42 peptide accumulated to higher levels in older-induced flies, and subsequently shortened lifespan only when induced at later timepoints. This difference correlated with an alteration in protein turnover with age [24]. Measurement of 35 S-Methionine incorporation showed that general protein translation was reduced in older flies, consistent with published studies showing that the rate of protein synthesis decreases with age in a wide variety of cells, tissues, organs and organisms, including humans (reviewed in [25]).…”

Section: Discussionsupporting

confidence: 64%

“…Protein turnover declines with age in several organisms [24,25], suggesting that age-dependent effects on protein synthesis or degradation could explain the accumulation of Ab42 peptide in older flies. As a measure of the rate of and measured by ELISA at the indicated time-points (n = 3).…”

Section: Age-dependent Reduction In Protein Turnover Correlates With mentioning

confidence: 99%

P1‐274: Ageing increases vulnerability to Aβ42 toxicity in drosophila

Kerr

Rogers

Martı́nez

et al. 2012

Alzheimer's & Dementia

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Age is the major risk factor for many neurodegenerative diseases, including Alzheimer's Disease (AD), for reasons that are not clear. The association could indicate that the duration or degree of exposure to toxic proteins is important for pathology, or that age itself increases susceptibility to protein toxicity. Using an inducible Drosophila model of AD, we investigated these possibilities by varying the expression of an Ab42 transgene in neurons at different adult ages and measuring the effects on Ab42 levels and associated pathological phenotypes. Acute induction of Arctic Ab42 in young adult flies resulted in rapid expression and clearance of mRNA and soluble Arctic Ab42 protein, but in irreversible expression of insoluble Arctic Ab42 peptide. Arctic Ab42 peptide levels accumulated with longer durations of induction, and this led to a dose-dependent reduction in negative geotaxis and lifespan. For a standardised level of mRNA expression, older flies had higher levels of Arctic Ab42 peptide and associated toxicity, and this correlated with an age-dependent reduction in proteasome activity. Equalising Ab42 protein at different ages shortened lifespan in correlation with the duration of exposure to the peptide, suggesting that Ab42 expression accumulates damage over time. However, the relative reduction in lifespan compared to controls was greater in flies first exposed to the peptide at older ages, suggesting that ageing itself also increases susceptibility to Ab42 toxicity. Indeed older flies were more vulnerable to chronic Ab42 toxicity even with a much lower lifetime exposure to the peptide. Finally, the persistence of insoluble Ab42 in both young and old induced flies suggests that aggregated forms of the peptide cause toxicity in later life. Our results suggest that reduced protein turnover, increased duration of exposure and increased vulnerability to protein toxicity at later ages in combination could explain the late age-of-onset of neurodegenerative phenotypes.

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“…Overexpression of HSPs (e.g., HSP70, HSP90, and small HSPs) by genetic technology extends lifespan in fruit flies [271], Caenorhabditis elegans [272, 273], and yeast [274], and protects against neurodegeneration in mice [275]. HSP accumulation in the nucleus after damage to the cell protects chromosome structure and function through limiting genomic instability [276] and preventing nuclear DAMP (e.g., HMGB1) release in response to oxidative injury and inflammatory stimuli [277, 278]. HSPs such as HSP70 can also inhibit TP53-dependnent and independent senescence as well as apoptosis.…”

Section: Damps At the Crossroads Of Ageing And Cancermentioning

confidence: 99%

DAMPs, ageing, and cancer: The ‘DAMP Hypothesis’

Huang

Xie

Sun

et al. 2015

Ageing Research Reviews

119

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Ageing is a complex and multifactorial process characterized by the accumulation of many forms of damage at the molecular, cellular, and tissue level with advancing age. Ageing increases the risk of the onset of chronic inflammation-associated diseases such as cancer, diabetes, stroke, and neurodegenerative disease. In particular, ageing and cancer share some common origins and hallmarks such as genomic instability, epigenetic alteration, aberrant telomeres, inflammation and immune injury, reprogrammed metabolism, and degradation system impairment (including within the ubiquitin-proteasome system and the autophagic machinery). Recent advances indicate that damage-associated molecular pattern molecules (DAMPs) such as high mobility group box 1, histones, S100, and heat shock proteins play location-dependent roles inside and outside the cell. These provide interaction platforms at molecular levels linked to common hallmarks of ageing and cancer. They can act as inducers, sensors, and mediators of stress through individual plasma membrane receptors, intracellular recognition receptors (e.g., advanced glycosylation end product-specific receptors, AIM2-like receptors, RIG-I-like receptors, and NOD1-like receptors, and toll-like receptors), or following endocytic uptake. Thus, the DAMP Hypothesis is novel and complements other theories that explain the features of ageing. DAMPs represent ideal biomarkers of ageing and provide an attractive target for interventions in ageing and age-associated diseases.

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Changes in protein turnover after heat shock are related to accumulation of abnormal proteins in aging Drosophila melanogaster

Cited by 16 publications

References 38 publications

Ageing Increases Vulnerability to Aβ42 Toxicity in Drosophila

Ageing Increases Vulnerability to Aβ42 Toxicity in Drosophila

P1‐274: Ageing increases vulnerability to Aβ42 toxicity in drosophila

DAMPs, ageing, and cancer: The ‘DAMP Hypothesis’

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