Drosophila models reveal novel insights into mechanisms underlying neurodegeneration

Mohan, Ryan D.; Workman, Jerry L.; Abmayr, Susan M.

doi:10.4161/19336934.2014.969150

Cited by 5 publications

(4 citation statements)

References 30 publications

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“…The Drosophila brain has been explored extensively to model neurodegenerative diseases (Chan and Bonini, 2000 ; Lu and Vogel, 2009 ). However, in contrast to mammals, the brain of Drosophila does not display obvious histological signs of neurodegeneration or apoptosis with increasing age, unless genetically manipulated or exposed to oxidative stress (see Chan and Bonini, 2000 ; White et al, 2010 ; Mohan et al, 2014 ). Only more subtle signs of aging have been revealed in the fly: central neurons do display some ultrastructural changes (Martín-Peña et al, 2006 ) and certain structural and molecular features were shown to be affected in axon terminations of motor neurons (Beramendi et al, 2007 ; Wagner et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Behavioral Senescence and Aging-Related Changes in Motor Neurons and Brain Neuromodulator Levels Are Ameliorated by Lifespan-Extending Reproductive Dormancy in Drosophila

Liao

Broughton

Nässel

2017

Front. Cell. Neurosci.

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The lifespan of Drosophila melanogaster can be extended substantially by inducing reproductive dormancy (also known as diapause) by lowered temperature and short days. This increase of longevity is accompanied by lowered metabolism and increased stress tolerance. We ask here whether behavioral senescence is ameliorated during adult dormancy. To study this we kept flies for seven or more weeks in normal rearing conditions or in diapause conditions and compared to 1-week-old flies in different behavioral assays of sleep, negative geotaxis and exploratory walking. We found that the senescence of geotaxis and locomotor behavior seen under normal rearing conditions was negligible in flies kept in dormancy. The normal senescence of rhythmic activity and sleep patterns during the daytime was also reduced by adult dormancy. Investigating the morphology of specific neuromuscular junctions (NMJs), we found that changes normally seen with aging do not take place in dormant flies. To monitor age-associated changes in neuronal circuits regulating activity rhythms, sleep and walking behavior we applied antisera to tyrosine hydroxylase (TH), serotonin and several neuropeptides to examine changes in expression levels and neuron morphology. In most neuron types the levels of stored neuromodulators decreased during normal aging, but not in diapause treated flies. No signs of neurodegeneration were seen in either condition. Our data suggest that age-related changes in motor neurons could be the cause of part of the behavioral senescence and that this is ameliorated by reproductive diapause. Earlier studies established a link between age-associated decreases in neuromodulator levels and behavioral decline that could be rescued by overexpression of neuromodulator. Thus, it is likely that the retained levels of neuromodulators in dormant flies alleviate behavioral senescence.

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Section: Introductionmentioning

confidence: 99%

Behavioral Senescence and Aging-Related Changes in Motor Neurons and Brain Neuromodulator Levels Are Ameliorated by Lifespan-Extending Reproductive Dormancy in Drosophila

Liao

Broughton

Nässel

2017

Front. Cell. Neurosci.

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“…Here, we find CP190 chromatin binding to be strongly correlated with Gcn5 genome-wide. Gcn5 is a highly conserved acetyltransferase, which is a component of the SAGA chromatin-modifying complex (for reviews see ( 38 , 51 )). Deficiencies of SAGA components cause severe developmental defects, suggesting that SAGA and Gcn5 contribute to the transcriptional regulation of developmental genes.…”

Section: Discussionmentioning

confidence: 99%

Chromatin binding of Gcn5 in Drosophila is largely mediated by CP190

Ali

Krüger

Bhuju

et al. 2016

Nucleic Acids Research

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Centrosomal 190 kDa protein (CP190) is a promoter binding factor, mediates long-range interactions in the context of enhancer-promoter contacts and in chromosomal domain formation. All Drosophila insulator proteins bind CP190 suggesting a crucial role in insulator function. CP190 has major effects on chromatin, such as depletion of nucleosomes, high nucleosomal turnover and prevention of heterochromatin expansion. Here, we searched for enzymes, which might be involved in CP190 mediated chromatin changes. Eighty percent of the genomic binding sites of the histone acetyltransferase Gcn5 are colocalizing with CP190 binding. Depletion of CP190 reduces Gcn5 binding to chromatin. Binding dependency was further supported by Gcn5 mediated co-precipitation of CP190. Gcn5 is known to activate transcription by histone acetylation. We used the dCas9 system to target CP190 or Gcn5 to a Polycomb repressed and H3K27me3 marked gene locus. Both, CP190 as well as Gcn5, activate this locus, thus supporting the model that CP190 recruits Gcn5 and thereby activates chromatin.

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“…The number of transgenic models of overexpression of disease-related proteins has been greatly expanded as to include a large panel of diseases and proteinopathies [5,8,10] including Alzheimer's disease [15], Parkinson's disease [38], polyglutamine expansion disorders such as Hunttington's disease [14], spinocerebellar ataxias [11], amyotrophic lateral sclerosis [6].…”

Section: Drosophila and The Study Of Neurodegenerationmentioning

confidence: 99%

“…A brief overview only of the major results obtained in recent years with these models will be given here and the reader is referred to excellent recent reviews for more detailed accounts on the progress made in modelling specific diseases [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

The promises of neurodegenerative disease modeling

Lepesant

2015

Comptes Rendus. Biologies

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The rise in the prevalence of neurodegenerative diseases parallels the rapid increase in human lifespan. Despite intensive research, the molecular and cellular mechanisms underlying the onset and progression of these devastating diseases with age are still poorly understood. Many aspects of these diseases have been modelled successfully in experimental animals such as the mouse, the zebrafish Brachydanio rero, the nematode worm Caenorhaditis elegans and the fruit fly Drosophila melanogaster. This review will focus on the advantages offered by the genetic tools available in Drosophila for combining powerful strategies in order to tackle the causative factors of these complex pathologies and help to elaborate efficient drugs to treat them.

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Drosophila models reveal novel insights into mechanisms underlying neurodegeneration

Cited by 5 publications

References 30 publications

Behavioral Senescence and Aging-Related Changes in Motor Neurons and Brain Neuromodulator Levels Are Ameliorated by Lifespan-Extending Reproductive Dormancy in Drosophila

Behavioral Senescence and Aging-Related Changes in Motor Neurons and Brain Neuromodulator Levels Are Ameliorated by Lifespan-Extending Reproductive Dormancy in Drosophila

Chromatin binding of Gcn5 in Drosophila is largely mediated by CP190

The promises of neurodegenerative disease modeling

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