Endoplasmic reticulum stress in disease: mechanisms and therapeutic opportunities

Hosoi, Toru; Ozawa, Koichiro

doi:10.1042/cs20080680

Cited by 152 publications

(118 citation statements)

References 115 publications

(130 reference statements)

Supporting

Mentioning

114

Contrasting

Unclassified

Order By: Relevance

“…Chronic activation of the UPR has been linked to a number of major diseases and conditions including diabetes, heart diseases, neurodegenerative diseases and aging (Marciniak and Ron, 2006;Scheper and Hoozemans, 2009). Therefore, modulation of the UPR is an emerging focus for developing therapeutics (Hosoi and Ozawa, 2010;Ozcan et al, 2006). …”

Section: Introductionmentioning

confidence: 99%

Changes in BiP availability reveal hypersensitivity to acute endoplasmic reticulum stress in cells expressing mutant huntingtin

Lajoie

Snapp

2011

Journal of Cell Science

View full text Add to dashboard Cite

Huntington's disease (HD) is caused by expanded glutamine repeats within the huntingtin (Htt) protein. Mutant Htt (mHtt) in the cytoplasm has been linked to induction of the luminal endoplasmic reticulum (ER) stress pathway, the unfolded protein response (UPR). How mHtt impacts the susceptibility of the ER lumen to stress remains poorly understood. To investigate molecular differences in the ER in cells expressing mHtt, we used live-cell imaging of a sensitive reporter of the misfolded secretory protein burden, GFP fused to the ER chaperone BiP (also known as GRP78), which decreases in mobility as it binds increasing amounts of misfolded proteins. Striatal neurons expressing full-length mHtt showed no differences in BiP–GFP mobility and no evidence of UPR activation compared with wild-type cells at steady state. However, mHtt-expressing cells were acutely sensitive to misfolded secretory proteins. Treatment with ER stressors, tunicamycin or DTT, rapidly decreased BiP–GFP mobility in mHtt striatal cells and accelerated UPR activation compared with wild-type cells. mHtt-expressing cells exhibited decreased misfolded protein flux as a result of ER associated degradation (ERAD) dysfunction. Furthermore, UPR-adapted mHtt cells succumbed to misfolded protein stresses that could be tolerated by adapted wild-type cells. Thus, mHtt expression impairs misfolded secretory protein turnover, decreases the ER stress threshold, and increases cell vulnerability to insults.

show abstract

Section: Introductionmentioning

confidence: 99%

Changes in BiP availability reveal hypersensitivity to acute endoplasmic reticulum stress in cells expressing mutant huntingtin

Lajoie

Snapp

2011

Journal of Cell Science

View full text Add to dashboard Cite

show abstract

“…ER stress triggers an evolutionarily conserved response, called unfolded protein response (UPR) (22,24). Three ER stress transducers have been identified: protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor (ATF) 6 (13,36). The initial activation of these sensors is dependent on the dissociation of Bip [also called glucose regulated protein 78 (GRP78)], the ER chaperone (13,22).…”

mentioning

confidence: 99%

Brain ACE2 overexpression reduces DOCA-salt hypertension independently of endoplasmic reticulum stress

Xia

Queiroz

Sriramula

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

View full text Add to dashboard Cite

-Endoplasmic reticulum (ER) stress was previously reported to contribute to neurogenic hypertension while neuronal angiotensin-converting enzyme type 2 (ACE2) overexpression blunts the disease. To assess which brain regions are important for ACE2 beneficial effects and the contribution of ER stress to neurogenic hypertension, we first used transgenic mice harboring a floxed neuronal hACE2 transgene (SL) and tested the impact of hACE2 knockdown in the subfornical organ (SFO) and paraventricular nucleus (PVN) on deoxycorticosterone acetate (DOCA)-salt hypertension. SL and nontransgenic (NT) mice underwent DOCA-salt or sham treatment while infected with an adenoassociated virus (AAV) encoding Cre recombinase (AAV-Cre) or a control virus (AAV-green fluorescent protein) to the SFO or PVN. DOCA-salt-induced hypertension was reduced in SL mice, with hACE2 overexpression in the brain. This reduction was only partially blunted by knockdown of hACE2 in the SFO or PVN, suggesting that both regions are involved but not essential for ACE2 regulation of blood pressure (BP). DOCA-salt treatment did not increase the protein levels of ER stress and autophagy markers in NT mice, despite a significant increase in BP. In addition, these markers were not affected by hACE2 overexpression in the brain, despite a significant reduction of hypertension in SL mice. To further assess the role of ER stress in neurogenic hypertension, NT mice were infused intracerebroventricularlly with tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, during DOCA-salt treatment. However, TUDCA infusion failed to blunt the development of hypertension in NT mice. Our data suggest that brain ER stress does not contribute to DOCA-salt hypertension and that ACE2 blunts neurogenic hypertension independently of ER stress. neurogenic hypertension; central nervous system; blood pressure; angiotensin-converting enzyme type 2; deoxycorticosterone acetate THE BRAIN RENIN-ANGIOTENSIN system (RAS) plays a critical role in the regulation of blood pressure (BP) via its actions in various brain regions, such as subfornical organ (SFO), paraventricular nucleus (PVN), rostral ventrolateral medulla (RVLM), and nucleus tractus solitarius (NTS) (17). An overactivated brain RAS leads to the development of neurogenic hypertension at least in part by increasing sympathetic outflow, blunting the baroreflex sensitivity and stimulating vasopressin secretion (17). Angiotensin-converting enzyme type 2 (ACE2), a pivotal RAS component, has been found in many regions in the bran, including SFO and PVN (8). Numerous studies have shown that ACE2 has opposite properties to that of the classic RAS via its conversion of angiotensin (ANG) II into ANG-(1-7) (20). We previously reported that overexpression of ACE2 in the brain blunts the development of hypertension in several animal models (9, 31). However, it is not clear which brain regions might be more important for the preservation of ACE2 compensatory activity.

show abstract

“…Although cellular mechanisms like the UPR ER combat protein misfolding there is a link between the duration of UPR signaling and cell fate under ER stress (Hosoi and Ozawa, 2010). The main goal of our study was to better characterize the mechanism of action of several potent chemical suppressors of mTDP-43 neuronal toxicity to determine if they operate through conserved mechanisms in C. elegans and D. rerio.…”

Section: Discussionmentioning

confidence: 99%

Chemical Genetic Screens for TDP-43 Modifiers and ALS Drug Discovery

Drapeau¹,

Parker²,

Kabashi³

et al. 2015

View full text Add to dashboard Cite

Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information , 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE March 2015 REPORT TYPE PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) AND ADDRESS(ES) PERFORMING ORGANIZATION REPORT NUMBERUniversite de Montreal, L' 2900 Boul. Edouard-Montpetit Montreal H3T 1J4 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTOur objective was to screen libraries of several thousand compounds, including clinically approved drugs, for their ability to suppress the in vivo phenotypes observed in worm and fish models expressing mutant human TDP-43 related to ALS and validating hits in a mouse model. Our hypothesis was that chemical modifiers of TDP-43 in vivo function would provide new therapeutic approaches to ALS. Our screen of 3,750 FDA-approved compounds identified 20 active compounds, most of which were neuroleptics with the most potent being pimozide, as well as WithaferinA. In addition to the 4k FDA compounds, we screened 2k molecules that are structurally related to the neuroleptics as well as novel molecules. Also, we screened 4k novel derivatives of pimozide and identified several dozen active compounds. WithaferinA and pimozide were tested in TDP-43 and SOD1 mice. Results suggest that the beneficial effect of Withaferin A in mutant SOD1 mice may be due in part to an upregulation of heat shock proteins (Hsp27 and Hsp70) and to reduction in levels of misfolded SOD1 species. Motor behaviors were not significantly improved or possibly worsened by chronic treatment with pimozide. In addition, the spinal cord and brain of mice revealed and increase in TDP-43 aggregation, but no change in microgliosis, was noted. Neuromuscular transmission was improved acutely. Pimozide is being tested in an ALS clinical trial based on our neuromuscular biomarker. References……………………………………………………………………………. 18 SUBJECT TERMSAppendices INTRODUCTIONOur project was to screen libraries of small chemicals, including clinically approved drugs, for their ability to suppres...

show abstract

Endoplasmic reticulum stress in disease: mechanisms and therapeutic opportunities

Cited by 152 publications

References 115 publications

Changes in BiP availability reveal hypersensitivity to acute endoplasmic reticulum stress in cells expressing mutant huntingtin

Changes in BiP availability reveal hypersensitivity to acute endoplasmic reticulum stress in cells expressing mutant huntingtin

Brain ACE2 overexpression reduces DOCA-salt hypertension independently of endoplasmic reticulum stress

Chemical Genetic Screens for TDP-43 Modifiers and ALS Drug Discovery

Contact Info

Product

Resources

About