Pharmacologic Activation of Integrated Stress Response Kinases Inhibits Pathologic Mitochondrial Fragmentation DOI Open Access
Kelsey R. Baron, Samantha Oviedo,

Sophia Krasny

et al.

Published: Sept. 25, 2024

Excessive mitochondrial fragmentation is associated with the pathologic dysfunction implicated in pathogenesis of etiologically-diverse diseases, including many neurodegenerative disorders. The integrated stress response (ISR) – comprising four eIF2α kinases PERK, GCN2, PKR, and HRI a prominent stress-responsive signaling pathway that regulates morphology function to diverse types insult. This suggests pharmacologic, stress-independent activation ISR represents potential strategy mitigate human disease. Here, we show or GCN2 promotes adaptive elongation prevents induced by calcium ionophore ionomycin. Further, these reduces restores basal patient fibroblasts expressing pathogenic D414V variant pro-fusion GTPase MFN2 neurological dysfunctions ataxia, optic atrophy, sensorineural hearing loss. These results identify as prevent disease-relevant chemical genetic insults, further motivating pursuit highly selective kinase-activating compounds therapeutic diseases.

Language: Английский

White matter damage and degeneration in traumatic brain injury DOI Creative Commons
Regina C. Armstrong, Genevieve M. Sullivan, Daniel P. Perl

et al.

Trends in Neurosciences, Journal Year: 2024, Volume and Issue: 47(9), P. 677 - 692

Published: Aug. 10, 2024

Traumatic brain injury (TBI) is a complex condition that can resolve over time but all too often leads to persistent symptoms, and the risk of poor patient outcomes increases with aging. TBI damages neurons long axons within white matter tracts are critical for communication between regions; this causes slowed information processing neuronal circuit dysfunction. This review focuses on after multifactorial processes underlie damage, potential recovery, progression degeneration. A multiscale perspective across clinical preclinical advances presented encourage interdisciplinary insights from whole-brain neuroimaging down cellular molecular responses axons, myelin, glial cells tissue.

Language: Английский

Citations

5
Pharmacologic Activation of Integrated Stress Response Kinases Inhibits Pathologic Mitochondrial Fragmentation DOI Open Access
Kelsey R. Baron, Samantha Oviedo,

Sophia Krasny

et al.

Published: Jan. 16, 2025

Excessive mitochondrial fragmentation is associated with the pathologic dysfunction implicated in pathogenesis of etiologically-diverse diseases, including many neurodegenerative disorders. The integrated stress response (ISR) – comprising four eIF2α kinases PERK, GCN2, PKR, and HRI a prominent stress-responsive signaling pathway that regulates morphology function to diverse types insult. This suggests pharmacologic activation ISR represents potential strategy mitigate human disease. Here, we show or GCN2 promotes adaptive elongation prevents induced by calcium ionophore ionomycin. Further, reduces restores basal patient fibroblasts expressing pathogenic D414V variant pro-fusion GTPase MFN2 neurological dysfunctions ataxia, optic atrophy, sensorineural hearing loss. These results identify as prevent disease-relevant chemical genetic insults, further motivating pursuit highly selective kinase-activating compounds therapeutic diseases.

Language: Английский

Citations

0
Pharmacologic activation of integrated stress response kinases inhibits pathologic mitochondrial fragmentation DOI Creative Commons
Kelsey R. Baron, Samantha Oviedo,

Sophia Krasny

et al.

eLife, Journal Year: 2025, Volume and Issue: 13

Published: Feb. 12, 2025

Excessive mitochondrial fragmentation is associated with the pathologic dysfunction implicated in pathogenesis of etiologically diverse diseases, including many neurodegenerative disorders. The integrated stress response (ISR) – comprising four eIF2α kinases PERK, GCN2, PKR, and HRI a prominent stress-responsive signaling pathway that regulates morphology function to types insult. This suggests pharmacologic activation ISR represents potential strategy mitigate human disease. Here, we show or GCN2 promotes adaptive elongation prevents induced by calcium ionophore ionomycin. Further, reduces restores basal patient fibroblasts expressing pathogenic D414V variant pro-fusion GTPase MFN2 neurological dysfunctions, ataxia, optic atrophy, sensorineural hearing loss. These results identify as prevent disease-relevant chemical genetic insults, further motivating pursuit highly selective kinase-activating compounds therapeutic diseases.

Language: Английский

Citations

0
Pharmacologic Activation of Integrated Stress Response Kinases Inhibits Pathologic Mitochondrial Fragmentation DOI Creative Commons
Kelsey R. Baron, Samantha Oviedo,

Sophia Krasny

et al.

eLife, Journal Year: 2024, Volume and Issue: 13

Published: Sept. 25, 2024

Excessive mitochondrial fragmentation is associated with the pathologic dysfunction implicated in pathogenesis of etiologically diverse diseases, including many neurodegenerative disorders. The integrated stress response (ISR) - comprising four eIF2α kinases PERK, GCN2, PKR, and HRI a prominent stress-responsive signaling pathway that regulates morphology function to types insult. This suggests pharmacologic activation ISR represents potential strategy mitigate human disease. Here, we show or GCN2 promotes adaptive elongation prevents induced by calcium ionophore ionomycin. Further, reduces restores basal patient fibroblasts expressing pathogenic D414V variant pro-fusion GTPase MFN2 neurological dysfunctions, ataxia, optic atrophy, sensorineural hearing loss. These results identify as prevent disease-relevant chemical genetic insults, further motivating pursuit highly selective kinase-activating compounds therapeutic diseases.

Language: Английский

Citations

1
Pharmacologic Activation of Integrated Stress Response Kinases Inhibits Pathologic Mitochondrial Fragmentation DOI Creative Commons
Kelsey R. Baron, Samantha Oviedo,

Sophia Krasny

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 10, 2024

SUMMARY Excessive mitochondrial fragmentation is associated with the pathologic dysfunction implicated in pathogenesis of etiologically-diverse diseases, including many neurodegenerative disorders. The integrated stress response (ISR) – comprising four eIF2α kinases PERK, GCN2, PKR, and HRI a prominent stress-responsive signaling pathway that regulates morphology function to diverse types insult. This suggests pharmacologic activation ISR represents potential strategy mitigate human disease. Here, we show or GCN2 promotes adaptive elongation prevents induced by calcium ionophore ionomycin. Further, reduces restores basal patient fibroblasts expressing pathogenic D414V variant pro-fusion GTPase MFN2 neurological dysfunctions ataxia, optic atrophy, sensorineural hearing loss. These results identify as prevent disease-relevant chemical genetic insults, further motivating pursuit highly selective kinase-activating compounds therapeutic diseases.

Language: Английский

Citations

0
Pharmacologic Activation of Integrated Stress Response Kinases Inhibits Pathologic Mitochondrial Fragmentation DOI Open Access
Kelsey R. Baron, Samantha Oviedo,

Sophia Krasny

et al.

Published: Sept. 25, 2024

Excessive mitochondrial fragmentation is associated with the pathologic dysfunction implicated in pathogenesis of etiologically-diverse diseases, including many neurodegenerative disorders. The integrated stress response (ISR) – comprising four eIF2α kinases PERK, GCN2, PKR, and HRI a prominent stress-responsive signaling pathway that regulates morphology function to diverse types insult. This suggests pharmacologic, stress-independent activation ISR represents potential strategy mitigate human disease. Here, we show or GCN2 promotes adaptive elongation prevents induced by calcium ionophore ionomycin. Further, these reduces restores basal patient fibroblasts expressing pathogenic D414V variant pro-fusion GTPase MFN2 neurological dysfunctions ataxia, optic atrophy, sensorineural hearing loss. These results identify as prevent disease-relevant chemical genetic insults, further motivating pursuit highly selective kinase-activating compounds therapeutic diseases.

Language: Английский

Citations

0