Genotoxic stress in constitutive trisomies induces autophagy and the innate immune response via the cGAS-STING pathway

Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.

“…1b, c). The p62 abundance further increased upon treatment with an inhibitor of autophagosome-lysosome fusion Bafilomycin A1 (BafA1), confirming the existence of normal autophagic flux in the polysomic cells as previously reported ( 8, 18 ). The size and number of p62 bodies per cell surface area also increase in polysomic cells (Fig.…”

Section: Resultssupporting

confidence: 86%

“…Abundance of p62 in aneuploid cells scales with the amount of extra DNA. We and others have previously shown that aneuploid cells accumulate autophagy and lysosomal markers on both transcriptome and proteome levels (8,(14)(15)(16)18). Among the most abundant proteins within this category was the selective autophagy receptor p62, which forms highly abundant cytosolic p62-bodies in polysomic cells.…”

Section: Resultsmentioning

confidence: 91%

Aneuploidy-induced proteostasis disruption impairs mitochondrial functions and mediates aggregation of mitochondrial precursor proteins through SQSTM1/p62

Amponsah

¹

,

Bökenkamp

²

,

Lenhard

³

et al. 2024

Preprint

Self Cite

5

Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.

“…Other upstream regulators of autophagy could be involved, such as the cGAS-STING pathway (Krivega et al, 2021 ) or, as also observed in our dataset, p53-mediated activation of DRAM1 (Crighton et al, 2006 ) that can induce apoptosis by increasing BAX protein levels (Guan et al, 2015 ). Second, we confirmed the presence of activated p53 in aneuploid human embryos.…”

Section: Discussionsupporting

confidence: 85%

Complex aneuploidy triggers autophagy and p53-mediated apoptosis and impairs the second lineage segregation in human preimplantation embryos

Regin

¹

,

Lei

²

,

Deckersberg

³

et al. 2024

Elife

6

Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.

“…showed that in constitutively trisomic cell lines, upon deletion of cGAS and STING, the expression of TFEB (transcription factor EB), which is the master regulator of lysosomal biogenesis, and its target genes (LC3, p62, LAMP2) was reduced, when compared with diploid cells. The same results could be shown in trisomic human embryonic fibroblasts, suggesting that cGAS-STING is not only responsible for the induction of inflammation after CIN, but also transcriptionally upregulates autophagy in response to aneuploidy, as shown in cells from humans with down syndrome (116).…”

Section: Preventing the Spread Of Cin By Sterile Inflammationsupporting

confidence: 73%

Cell Death as a Barrier against CIN and Aneuploidy

Weiss

¹

,

Villunger

²

,

Gallob

³

et al. 2022

Preprint

1

Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.