<scp>FOXO</scp> protects against age‐progressive axonal degeneration

Hwang, Inah; Oh, Han; Santo, Evan E.; Kim, Do Yeon; Chen, John W.; Bronson, Roderick T.; Locasale, Jason W.; Na, Yoonmi; Lee, Jaclyn; Reed, Sandra M.; Tóth, Miklós; Yu, Wen H.; Muller, Florian L.; Paik, Jihye

doi:10.1111/acel.12701

Cited by 53 publications

(54 citation statements)

References 45 publications

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“…The miRWalk database predicted that miR‐200a might target FOXO3 3'‐UTR. FOXO expression is progressively increased in the aging brain to prevent axonal degeneration (Hwang et al, ). FOXO3 was confirmed to promote autophagy via various pathways (Warr et al, ; Zhou et al, ).…”

Section: Discussionmentioning

confidence: 99%

KCNQ1OT1 promotes autophagy by regulating miR‐200a/FOXO3/ATG7 pathway in cerebral ischemic stroke

et al. 2019

Aging Cell

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Dysregulation of long noncoding RNAs (lncRNAs) is associated with abnormal development and pathophysiology in the brain. Increasing evidence has indicated that ischemic stroke is becoming the most common cerebral disease in aging populations. The treatment of ischemic stroke is challenging, due in part to ischemia and reperfusion (I/R) injury. In this study, we revealed that potassium voltage‐gated channel subfamily Q member 1 opposite strand 1 (KCNQ1OT1) was significantly upregulated in ischemic stroke. Knockdown of KCNQ1OT1 remarkably reduced the infarct volume and neurological impairments in transient middle cerebral artery occlusion (tMCAO) mice. Mechanistically, KCNQ1OT1 acted as a competing endogenous RNA of miR‐200a to regulate downstream forkhead box O3 (FOXO3) expression, which is a transcriptional regulator of ATG7. Knockdown of KCNQ1OT1 might inhibit I/R‐induced autophagy and increase cell viability via the miR‐200a/FOXO3/ATG7 pathway. This finding offers a potential novel strategy for ischemic stroke therapy.

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Section: Discussionmentioning

confidence: 99%

KCNQ1OT1 promotes autophagy by regulating miR‐200a/FOXO3/ATG7 pathway in cerebral ischemic stroke

et al. 2019

Aging Cell

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“…Interestingly, FoxOs in these neurons suppress mTor signaling and maintain a level of autophagic flux that is necessary for the normal morphogenesis of the neurons. In addition, FoxOs were found to be upregulated in aged brains and function to delay aging-related axonal tract degeneration by suppressing mTor activity (Hwang et al, 2018). In Drosophila C4da neurons, FoxO was previously found to promote dendrite space-filling and to mediate polyQ-induced neuronal toxicity (Sears and Broihier, 2016; Kwon et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Low FoxO expression inDrosophilasomatosensory neurons protects dendrite growth under nutrient restriction

Poe

Zhang

et al. 2019

Preprint

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17During prolonged nutrient restriction, developing animals redistribute vital nutrients to favor brain 18 growth at the expense of other organs. In Drosophila, such brain sparing relies on a glia-derived growth 19 factor to sustain proliferation of neural stem cells. However, whether other aspects of neural 20 development are also spared under nutrient restriction is unknown. Here we show that dynamically 21 growing somatosensory neurons in the Drosophila peripheral nervous system exhibit organ sparing at 22 the level of arbor growth: Under nutrient stress, sensory dendrites preferentially grow as compared to 23 neighboring non-neural tissues, resulting in dendrite overgrowth. Underlying this neuronal nutrient-24 insensitivity is the lower expression of the stress sensor FoxO in neurons. Consequently, nutrient 25 restriction suppresses Tor signaling less and does not induce autophagy in neurons. Preferential dendrite 26 growth is functional desirable because it results in heightened animal responses to sensory stimuli, 27 indicative of a potential survival advantage under environmental challenges.28

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“…While this gene does not even have a prior TADA score in Nguyen et al [67], DeepND marks it as the 57 th risk gene. Deletion of FOXO transcription factors is shown to cause axonal degeneration and elevated mTORC1 activity [38] which was previously associated with several neurological and neurodevelopmental disorders including autism and epilepsy. Krishnan et al ranks this gene in the fifth decile and DAWN cannot capture it due to lack of correlation in prefrontal cortex during mid-fetal period.…”

Section: Identification Of Novel Candidates Within Asd and Id Associamentioning

confidence: 91%

Deep multitask learning of gene risk for comorbid neurodevelopmental disorders

Beyreli

Karakahya

Çiçek

2020

Preprint

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Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) are comorbid neurodevelopmental disorders with complex genetic architectures. Despite large-scale sequencing studies only a fraction of the risk genes were identified for both. Here, we present a novel network-based gene risk prioritization algorithm named DeepND that performs cross-disorder analysis to improve prediction power by exploiting the comorbidity of ASD and ID via multitask learning. Our model leverages information from gene coexpression networks that model human brain development using graph convolutional neural networks and learns which spatio-temporal neurovelopmental windows are important for disorder etiologies. We show that our approach substantially improves the state-of-the-art prediction power in both single-disorder and cross-disorder settings. DeepND identifies mediodorsal thalamus and cerebral cortex brain region and infancy to childhood period as the highest neurodevelopmental risk window for both ASD and ID. We observe that both disorders are enriched in transcription regulators. Despite tight regulatory links in between ASD risk genes, such is lacking across ASD and ID risk genes or within ID risk genes. Finally, we investigate frequent ASD and ID associated copy number variation regions and confident false findings to suggest several novel susceptibility gene candidates. DeepND can be generalized to analyze any combinations of comorbid disorders and is released at http://github.com/ciceklab/deepnd. # Equal contribution.*Correspondance: cicek@cs.bilkent.edu.tr been used to assess gene risk using excess genetic burden from case-control and family studies [35] which are recently extended to work with multiple traits [68]. Yet, these tools work with genes with observed disruptive mutations (mainly de novo). It is often of interest to use these as prior risk and obtain a posterior gene interaction network-adjusted risk which can also assess risk for genes with no prior signal. Network-based computational gene risk prediction methods come handy for (i) imputing the insufficient statistical signal and providing a genome-wide risk ranking, and (ii) finding out the affected cellular circuitries such as pathways and networks of genes [35,29,24,37,69,27,26,67,10]. While these methods have helped unraveling the underlying mechanisms, they have several limitations. First, by design, they are limited to work with a single disorder. In order to compare and contrast comorbid disorders such as ASD and ID using these tools, one approach is to bag the mutational burden observed for each disorder assuming two are the same. However, disorder specific features are lost as a consequence [29]. The more common approach is to perform independent analyses per disorder and intersect the results. Unfortunately, this approach ignores valuable source of information coming from the shared genetic architecture and lose prediction power as per-disorder analyses have less input (i.e., samples, mutation counts) and less statistical power [81,12,37]. Second, c...

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FOXO protects against age‐progressive axonal degeneration

Cited by 53 publications

References 45 publications

KCNQ1OT1 promotes autophagy by regulating miR‐200a/FOXO3/ATG7 pathway in cerebral ischemic stroke

KCNQ1OT1 promotes autophagy by regulating miR‐200a/FOXO3/ATG7 pathway in cerebral ischemic stroke

Low FoxO expression inDrosophilasomatosensory neurons protects dendrite growth under nutrient restriction

Deep multitask learning of gene risk for comorbid neurodevelopmental disorders

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