A Functional Misexpression Screen Uncovers a Role for Enabled in Progressive Neurodegeneration

Rezával, Carolina; Berni, Jimena; Gorostiza, Ezequiel Axel; Werbajh, Santiago; Fagilde, María Marta; Fernández, María Paz; Beckwith, Esteban J.; Aranovich, Ezequiel J.; García, Carmen A. Sabio y; Ceriani, M. Fernanda

doi:10.1371/journal.pone.0003332

Cited by 21 publications

(26 citation statements)

References 60 publications

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“…Males were monitored for 3 d in LD 12:12 followed by 7 d in DD. We observed that the activity of aging flies was fragmented and extended into the night in LD (Figure 1A), similar to previous reports (Koh et al, 2006; Rezaval et al, 2008). Analysis of fly activity in DD revealed decreased proportion of rhythmic flies in 35- and 50-day-old flies (Figure 1B).…”

Section: Resultssupporting

confidence: 92%

“…We addressed this question using Drosophila , which are short-lived and have a well-understood circadian system. First, we confirmed previous reports of deterioration of the circadian locomotor activity rhythm in aging flies (Koh et al, 2006; Rezaval et al, 2008). In our study, flies that remained rhythmic in DD showed significant lengthening of the free-running period of locomotor activity.…”

Section: Discussionsupporting

confidence: 90%

“…In our study, flies that remained rhythmic in DD showed significant lengthening of the free-running period of locomotor activity. Although the previous study on aging flies reported a similar tendency, period length did not show a statistically significant difference (Rezaval et al, 2008). Interestingly, one of the studies examining the period of wheel-running activity as a function of age in mammals reported significant lengthening of the free-running period in 2-year-old mice (Valentinuzzi et al, 1997).…”

Section: Discussionmentioning

confidence: 55%

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Effects of Aging on the Molecular Circadian Oscillations inDrosophila

Rakshit

Krishnan

Guzik

et al. 2012

Chronobiology International

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Circadian clocks maintain temporal homeostasis by generating daily output rhythms in molecular, cellular, and physiological functions. Output rhythms, such as sleep/wake cycles and hormonal fluctuations, tend to deteriorate during aging in humans, rodents, and fruit flies. However, it is not clear whether this decay is caused by defects in the core transcriptional clock, or weakening of the clock-output pathways, or both. The authors monitored age-related changes in behavioral and molecular rhythms in Drosophila melanogaster. Aging was associated with disrupted rest/activity patterns and lengthening of the free-running period of the circadian locomotor activity rhythm. The expression of core clock genes was measured in heads and bodies of young, middle-aged, and old flies. Transcriptional oscillations of four clock genes, period, timeless, Par domain protein 1ε, and vrille, were significantly reduced in heads, but not in bodies, of aging flies. It was determined that reduced transcription of these genes was not caused by the deficient expression of their activators, encoded by Clock and cycle genes. Interestingly, transcriptional activation by CLOCK-CYCLE complexes was impaired despite reduced levels of the PERIOD repressor protein in old flies. These data suggest that aging alters the properties of the core transcriptional clock in flies such that both the positive and the negative limbs of the clock are attenuated.

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Section: Resultssupporting

confidence: 92%

Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 55%

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Effects of Aging on the Molecular Circadian Oscillations inDrosophila

Rakshit

Krishnan

Guzik

et al. 2012

Chronobiology International

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“…The links between AD and circadian rhythms were inferred from transgenic model animals expressing pathogenic versions of human genes (Rezaval et al, 2008; Roh et al, 2012; Sterniczuk et al, 2010). Recent reports showed that pathogenic human amyloid peptides disrupt behavioral rest-activity rhythms in Drosophila but are not sufficient to disrupt molecular oscillations of PERIOD (PER) in central pacemaker neurons (Chen et al, 2014; Long et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Manipulations of amyloid precursor protein cleavage disrupt the circadian clock in aging Drosophila

Blake

Holbrook

Kotwica‐Rolinska

et al. 2015

Neurobiology of Disease

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Alzheimer’s disease (AD) is a neurodegenerative disease characterized by severe cognitive deterioration. While causes of AD pathology are debated, a large body of evidence suggests that increased cleavage of Amyloid Precursor Protein (APP) producing the neurotoxic Amyloid-β (Aβ) peptide plays a fundamental role in AD pathogenesis. One of the detrimental behavioral symptoms commonly associated with AD is the fragmentation of sleep-activity cycles with increased nighttime activity and daytime naps in humans. Sleep-activity cycles, as well as physiological and cellular rhythms, which may be important for neuronal homeostasis, are generated by a molecular system known as the circadian clock. Links between AD and the circadian system are increasingly evident but not well understood. Here we examined whether genetic manipulations of APP-like (APPL) protein cleavage in Drosophila melanogaster affect rest-activity rhythms and core circadian clock function in this model organism. We show that the increased β-cleavage of endogenous APPL by the β-secretase (dBACE) severely disrupts circadian behavior and leads to reduced expression of clock protein PER in central clock neurons of aging flies. Our data suggest that behavioral rhythm disruption is not a product of APPL-derived Aβ production but rather may be caused by a mechanism common to both α and β-cleavage pathways. Specifically, we show that increased production of the endogenous Drosophila Amyloid Intracellular Domain (dAICD) caused disruption of circadian rest-activity rhythms, while flies overexpressing endogenous APPL maintained stronger circadian rhythms during aging. In summary, our study offers a novel entry point toward understanding the mechanism of circadian rhythm disruption in Alzheimer’s disease.

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“…Secondary antibodies (1:250; Jackson ImmunoResearch) were Cy2-conjugated donkey anti-rat, Cy5-conjugated donkey anti-mouse and Cy3-conjugated donkey anti-rabbit. Incubation was for 3 h at 23 C, and the brains were then rinsed 5 times in PT for 25 min each followed by a long rinse overnight a 4 C. Brains were mounted in 80% glycerol in PT (Rezával et al, 2008).…”

Section: Dissections and Immunofluorescencementioning

confidence: 99%