Inhibition of oxidative stress in cholinergic projection neurons fully rescues aging-associated olfactory circuit degeneration in Drosophila

Hussain, Ashiq; Pooryasin, Atefeh; Zhang, Mo; Loschek, Laura F.; Fortezza, Marco La; Friedrich, Anja; Blais, Catherine; Üçpunar, Habibe K.; Yépez, Vicente A.; Lehmann, Martin; Gompel, Nicolas; Gagneur, Julien; Sigrist, Stephan J.; Kadow, Ilona C. Grunwald

doi:10.7554/elife.32018

Cited by 32 publications

(32 citation statements)

References 39 publications

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“…Increased oxidative stress is commonly associated with ageing [56][57][58] . We first treated flies with a low dose of paraquat (PQ) to mimic oxidative stress [59][60][61][62][63] .…”

Section: Exogenous Dna Damage Leads To Increased Polyploidymentioning

confidence: 99%

Polyploidy in the adultDrosophilabrain

Nandakumar

Grushko

Buttitta

2019

Preprint

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Long-lived cells such as terminally differentiated postmitotic neurons and glia must cope with the accumulation of damage over the course of an animal's lifespan. How long-lived cells deal with ageing-related damage is poorly understood. Here we show that polyploid cells accumulate in the ageing adult fly brain and that polyploidy protects against DNA damage-induced cell death. Multiple types of neurons and glia that are diploid at eclosion, become polyploid with age in the adult Drosophila brain. The optic lobes exhibit the highest levels of polyploidy, associated with an elevated DNA damage response in this brain region with age. Inducing oxidative stress or exogenous DNA damage leads to an earlier onset of polyploidy, and polyploid cells in the adult brain are more resistant to DNA damage-induced cell death than diploid cells. Our results suggest polyploidy may serve a protective role for neurons and glia in ageing Drosophila melanogaster brains. for providing fly stocks, particularly the labs of Cheng-

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“…Increased oxidative stress is commonly associated with ageing [56][57][58] . We first treated flies with a low dose of paraquat (PQ) to mimic oxidative stress [59][60][61][62][63] .…”

Section: Exogenous Dna Damage Leads To Increased Polyploidymentioning

confidence: 99%

Polyploidy in the adultDrosophilabrain

Nandakumar

Grushko

Buttitta

2019

Preprint

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“…Molecular signals found to be changed during aging are sometimes also altered in neurodegenerative diseases (Colacurcio & Nixon, ; Jagust, ; Winick‐Ng & Rylett, ). There are many similarities between an aged animal and an animal with a neurodegenerative disease; for instance, (a) accumulated oxidative stress is observed in both animals (Hernández‐Camacho, Bernier, López‐Lluch & Navas, ; Hussain et al., ; Prolla & Mattson, ), (b) the requirement of nutrition is increased (Harding, Gonder, Robinson, Crean & Singhrao, ; Prolla & Mattson, ), (c) learning and memory performance decline, and (d) multicellular signals are altered in the brain. However, whether there is one common cellular pathway that links and regulates both aging‐related pathologies and neurodegenerative diseases remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Aging‐induced Akt activation involves in aging‐related pathologies and Aβ‐induced toxicity

Chen

Hsieh

et al. 2019

Aging Cell

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Multicellular signals are altered in the processes of both aging and neurodegenerative diseases, including Alzheimer's disease (AD). Similarities in behavioral and cellular functional changes suggest a common regulator between aging and AD that remains undetermined. Our genetics and behavioral approaches revealed the regulatory role of Akt in both aging and AD pathogenesis. In this study, we found that the activity of Akt is upregulated during aging through epidermal growth factor receptor activation by using the fruit fly as an in vivo model. Downregulation of Akt in neurons improved cell survival, locomotor activity, and starvation challenge in both aged and Aβ42‐expressing flies. Interestingly, increased cAMP levels attenuated both Akt activation‐induced early death and Aβ42‐induced learning deficit in flies. At the molecular level, overexpression of Akt promoted Notch cleavage, suggesting that Akt is an endogenous activity regulator of γ‐secretase. Taken together, this study revealed that Akt is involved in the aging process and Aβ toxicity, and manipulating Akt can restore both neuronal functions and improve behavioral activity during the processes of aging and AD pathogenesis.

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“…We therefore asked how changes in the number of presynaptic filopodia, that result from changes in Jeb-Alk signaling, might impact on synapse formation between central neurons (Fig 2F-H). To this end we established the first verified postsynaptic reporter for central neurons in Drosophila ; DNA fragmentation factor related protein 2 (Drep2) has previously been suggested to be postsynaptically localized in Kenyon cells 37, 38 . Using expansion microscopy (ExM, 39, 40 and a novel dFLEx YPet allele for tagging the endogenous active zone protein Bruchpilot (Brp FOnYPet , Fig S3A), we could confirm that Drep2 profiles (anti-Drep2) in the VNC are juxtaposed to Brp YPet marked presynaptic release sites.…”

Section: Resultsmentioning

confidence: 99%

Motor circuit function is stabilized during postembryonic growth by anterograde trans-synaptic Jelly Belly - Anaplastic Lymphoma Kinase signaling

Gärtig

Ostrovsky

Manhart

et al. 2019

Preprint

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SummaryThe brain adapts to a changing environment or growing body size by structural growth and synaptic plasticity. Mechanisms studied to date promote synaptic growth between partner neurons, while negative counterparts that inhibit such interactions have so far remained elusive. Here, we investigate the role of Jeb-Alk signaling in coordinating motor circuit growth during larval stages of Drosophila. We quantify neuronal growth dynamics by intra-vital imaging, and synaptogenesis at nanometer resolution using endogenously labeled synaptic proteins, conditionally tagged with a fluorophore, and link changes in circuit anatomy with altered synaptic physiology and behavior. We find that loss of Jeb-Alk signaling leads to increased strengthening of synaptic excitation by developmental addition of additional postsynaptic but not pre-synaptic specializations. These changes ultimately lead to an epilepsy-like seizure behavior. We thus demonstrate that trans-synaptic anterograde Jeb-Alk signaling acts to stabilize developmental plasticity and circuit function, and that it does so specifically during postembryonic growth.

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Inhibition of oxidative stress in cholinergic projection neurons fully rescues aging-associated olfactory circuit degeneration in Drosophila

Cited by 32 publications

References 39 publications

Polyploidy in the adultDrosophilabrain

Polyploidy in the adultDrosophilabrain

Aging‐induced Akt activation involves in aging‐related pathologies and Aβ‐induced toxicity

Motor circuit function is stabilized during postembryonic growth by anterograde trans-synaptic Jelly Belly - Anaplastic Lymphoma Kinase signaling

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