Abstract
Endoplasmic reticulum (ER) stress is a prominent cellular alteration of diseases impacting the nervous system that are associated to the accumulation of misfolded and aggregated protein species during aging. The unfolded protein response (UPR) is the main pathway mediating adaptation to ER stress, but it can also trigger deleterious cascades of inflammation and cell death leading to cell dysfunction and neurodegeneration. Genetic and pharmacological studies in experimental models shed light into molecular pathways possibly contributing to ER stress and the UPR activation in human neuropathies. Most of experimental models are, however, based on the overexpression of mutant proteins causing familial forms of these diseases or the administration of neurotoxins that induce pathology in young animals. Whether the mechanisms uncovered in these models are relevant for the etiology of the vast majority of age-related sporadic forms of neurodegenerative diseases is an open question. Here, we provide a systematic analysis of the current evidence linking ER stress to human pathology and the main mechanisms elucidated in experimental models. Furthermore, we highlight the recent association of metabolic syndrome to increased risk to undergo neurodegeneration, where ER stress arises as a common denominator in the pathogenic crosstalk between peripheral organs and the nervous system.
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Abbreviations
- AD:
-
Alzheimer’s disease
- AgRP:
-
agouti-related protein
- ALS:
-
amyotrophic lateral sclerosis
- APP:
-
amyloid precursor protein
- ASK1:
-
apoptosis signal-regulating kinase 1
- ATF4:
-
activating transcription factor 4
- ATF6:
-
activating transcription factor 6
- ATF6f:
-
ATF6 fragment
- BDNF:
-
brain-derived neurotrophic factor
- BiP:
-
binding-immunoglobulin protein
- CHOP:
-
C/EBP homologous protein
- CNS:
-
central nervous system
- Canx:
-
calnexin
- CREB:
-
c-AMP response element-binding protein
- Calr:
-
calreticulin
- DBM:
-
dibenzoylmethane
- EDEM:
-
endoplasmic reticulum degradation-enhancing α-mannosidase-like protein
- eIF2α:
-
eukaryotic initiation factor 2α
- ER:
-
endoplasmic reticulum
- ERAD:
-
endoplasmic reticulum-associated protein degradation
- ERp57:
-
endoplasmic reticulum-related protein 57
- FoxO1:
-
Forkhead box protein O1
- FUS:
-
fused in sarcoma
- GADD34:
-
growth arrest and DNA damage-inducible protein 34
- GalE:
-
UDP-galactose-4-epimerase
- GSK3β:
-
glycogen synthase kinase 3β
- GT1:
-
UDP-glucose:glycoprotein glucosyltransferase
- HD:
-
Huntington’s disease
- HERPUD1:
-
homocysteine-responsive ER-resident ubiquitin-like domain member 1 protein
- HFD:
-
high-fat-diet
- HIPK2:
-
homeodomain-interacting protein kinase 2
- IκB:
-
inhibitor of NF-κB
- IKK:
-
inhibitor of NF-κB kinase
- IL-1β:
-
interleukin 1β
- iNOS:
-
inducible nitric oxide synthase
- IRE1α:
-
Inositol-requiring enzyme 1α
- ISR:
-
integrated stress response
- ISRIB:
-
integrated stress response inhibitor
- JNK:
-
c-Jun N-terminal kinase
- KIRA:
-
kinase inhibitor RNase attenuator
- MSA:
-
multiple system atrophy
- α-MSH:
-
α-melanocyte-stimulating hormone
- NF-κB:
-
nuclear factor-κB
- NLRP3:
-
nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain-containing 3
- 4-PBA:
-
4-phenybutyrate
- PD:
-
Parkinson’s disease
- PDI:
-
protein disulfide isomerase
- PERK:
-
PKR-like endoplasmic reticulum kinase
- PI3K:
-
phosphoinositide 3-kinases
- PMD:
-
protein misfolding disorder
- POMC:
-
pro-opiomelanocortin
- PPI:
-
protein phosphatase 1
- PRD:
-
prion-related disorder
- RIDD:
-
regulated IRE1-dependent decay
- RTCB:
-
RNA 2′,3′-cyclic phosphate and 5’-OH ligase
- S1P:
-
site-1 protease
- S2P:
-
site-2 protease
- SIL1:
-
nucleotide exchanging factor for BiP
- SOCS3:
-
suppressor of cytokine signaling 3
- SOD1:
-
superoxide dismutase 1
- TARDBP:
-
TAR DNA binding protein
- TNF:
-
tumor necrosis factor
- TRAF2:
-
TNF receptor-associated factor 2
- TXNIP:
-
thioredoxin-interacting protein
- UPR:
-
unfolded protein response
- UPS:
-
ubiquitin proteasome system
- VCP:
-
valosin-containing protein
- XBP1:
-
X-box binding protein 1
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Acknowledgements
This work was funded by FONDECYT 1191538, Muscular Dystrophy Association 575897 and ALS Association 19-IIA-456 (DBM), FONDECYT 3180427 (YH), and FONDECYT 1140549, FONDAP program 15150012, Millennium Institute P09-015-F, European Commission R&D MSCA-RISE 734749, FONDEF ID16I10223, FONDEF ID11E1007, CONICYT-Brazil 441921/2016-7, Michael J Fox Foundation for Parkinson’s Research—Target Validation grant 9277, US Office of Naval Research-Global N62909-16-1-2003, US Air Force Office of Scientific Research FA9550-21-1-0096, Department of Defense ALS Research Program Award 81XWH-16-1-0112 and Muscular Dystrophy Association 382453 (CH).
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Medinas, D.B., Hazari, Y., Hetz, C. (2021). Disruption of Endoplasmic Reticulum Proteostasis in Age-Related Nervous System Disorders. In: Agellon, L.B., Michalak, M. (eds) Cellular Biology of the Endoplasmic Reticulum . Progress in Molecular and Subcellular Biology, vol 59. Springer, Cham. https://doi.org/10.1007/978-3-030-67696-4_12
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