The genomic landscape of human cellular circadian variation points to a novel role for the signalosome

Gaspar, Ludmila; Howald, Cédric; Popadin, Konstantin; Maier, Bert; Mauvoisin, Daniel; Moriggi, Ermanno; Gutiérrez‐Arcelus, María; Falconnet, Emilie; Borel, Christelle; Kunz, Dieter; Kramer, Achim; Gachon, Frédéric; Dermitzakis, Emmanouil T.; Antonarakis, Stylianos E.; Brown, Steven A.

doi:10.7554/elife.24994

Cited by 12 publications

(10 citation statements)

References 63 publications

(90 reference statements)

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“…The control exosomes contain components of the proteasome complex consisting of a cluster of hub proteins consisting of PSMC1, PSMC4, and PMSD11 regulatory subunits of the 26S proteasome − (Table ). This cluster interacts with COPS2, COPS3, and COPS7B − (Figure ), components of the COP9 signalosome complex, , which is involved in the ubiquitin conjugation pathway through the regulation of E3 ligase complexes for the regulation of ubiquitin-targeted proteasome degradation of proteins. ,, …”

Section: Resultsmentioning

confidence: 99%

Mutant Presenilin 1 Dysregulates Exosomal Proteome Cargo Produced by Human-Induced Pluripotent Stem Cell Neurons

et al. 2021

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The accumulation and propagation of hyperphosphorylated tau (p-Tau) is a neuropathological hallmark occurring with neurodegeneration of Alzheimer’s disease (AD). Extracellular vesicles, exosomes, have been shown to initiate tau propagation in the brain. Notably, exosomes from human-induced pluripotent stem cell (iPSC) neurons expressing the AD familial A246E mutant form of presenilin 1 (mPS1) are capable of inducing tau deposits in the mouse brain after in vivo injection. To gain insights into the exosome proteome cargo that participates in propagating tau pathology, this study conducted proteomic analysis of exosomes produced by human iPSC neurons expressing A246E mPS1. Significantly, mPS1 altered the profile of exosome cargo proteins to result in (1) proteins present only in mPS1 exosomes and not in controls, (2) the absence of proteins in the mPS1 exosomes which were present only in controls, and (3) shared proteins which were upregulated or downregulated in the mPS1 exosomes compared to controls. These results show that mPS1 dysregulates the proteome cargo of exosomes to result in the acquisition of proteins involved in the extracellular matrix and protease functions, deletion of proteins involved in RNA and protein translation systems along with proteasome and related functions, combined with the upregulation and downregulation of shared proteins, including the upregulation of amyloid precursor protein. Notably, mPS1 neuron-derived exosomes displayed altered profiles of protein phosphatases and kinases involved in regulating the status of p-tau. The dysregulation of exosome cargo proteins by mPS1 may be associated with the ability of mPS1 neuron-derived exosomes to propagate tau pathology.

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Section: Resultsmentioning

confidence: 99%

Mutant Presenilin 1 Dysregulates Exosomal Proteome Cargo Produced by Human-Induced Pluripotent Stem Cell Neurons

et al. 2021

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“…In the meantime, he joined Achim Kramer’s lab as a Humboldt Fellow. This collaboration resulted in a close friendship between Steve and Achim and 4 high-impact publications during and after Steve’s sabbatical in Berlin (Brown et al, 2008; Kowalska et al, 2012; Azzi et al, 2014; Gaspar et al, 2017) that paved the way to further molecular studies of human oscillators and their outputs (Dallmann et al, 2012; Gaspar et al, 2014; Gaspar and Brown, 2015). Not surprisingly, Steve’s research career as an independent investigator was highly successful.…”

Section: Steve the Professor And Mentormentioning

confidence: 99%

Steve Brown

Schibler¹,

Dibner²,

Ripperger³

2023

J Biol Rhythms

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“…Interestingly, a recent study has shown overlap between genetic predisposition for eveningness and bipolar disorder (Melroy-Greif, Gizer, Wilhelmsen, & Ehlers, 2017). Importantly, another recent study using umbilical fibroblast have shown that factors associated with protein turnover are associated with chronotype, indicating that circadian clock-non-specific factors may be important in influencing clock dynamics and shaping chronotype (Gaspar et al, 2017).…”

Section: Chronotype Clock Genes and Adhdmentioning

confidence: 99%

ADHD 24/7: Circadian clock genes, chronotherapy and sleep/wake cycle insufficiencies in ADHD

Korman

Palm

Uzoni

et al. 2018

The World Journal of Biological Psychiatry

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Objectives. The current paper addresses the evidence for circadian clock characteristics associated with Attention-Deficit Hyperactivity Disorder (ADHD), and possible therapeutic approaches based on chronomodulation through bright light therapy. Methods. We review the data reported in ADHD on genetic risk factors for phase-delayed circadian rhythms and on the role of photic input in circadian realignment. Results. Single nucleotide polymorphisms (SNPs) in circadian genes were recently associated with core ADHD symptoms, increased evening-orientation and frequent sleep problems. Additionally, alterations in exposure and response to photic input may underlie circadian problems in ADHD. Bright light (BL) therapy was shown to be effective for realignment of circadian physiology toward morningness, reducing sleep disturbances and bringing overall improvement in ADHD symptoms. The susceptibility of the circadian system to phase shift by timed BL exposure may have broad cost-effective potential implications for the treatment of ADHD. Conclusions. We conclude that further research of circadian function in ADHD should focus on detection of genetic markers (e.g., using human skin fibroblasts) and development of BLbased therapeutic interventions.

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The genomic landscape of human cellular circadian variation points to a novel role for the signalosome

Cited by 12 publications

References 63 publications

Mutant Presenilin 1 Dysregulates Exosomal Proteome Cargo Produced by Human-Induced Pluripotent Stem Cell Neurons

Mutant Presenilin 1 Dysregulates Exosomal Proteome Cargo Produced by Human-Induced Pluripotent Stem Cell Neurons

Steve Brown

ADHD 24/7: Circadian clock genes, chronotherapy and sleep/wake cycle insufficiencies in ADHD

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