Abstract
Endoplasmic reticulum (ER) stress is caused by disturbances in the structure and function of the ER with the accumulation of misfolded proteins and alterations in the calcium homeostasis. The ER response is characterized by changes in specific proteins, causing translational attenuation, induction of ER chaperones and degradation of misfolded proteins. In case of prolonged or aggravated ER stress, cellular signals leading to cell death are activated. ER stress has been suggested to be involved in some human neuronal diseases, such as Parkinson's disease, Alzheimer's and prion disease, as well as other disorders. The exact contributions to and casual effects of ER stress in the various disease processes, however, are not known. Here we will discuss the possible role of ER stress in neurodegenerative diseases, and highlight current knowledge in this field that may reveal novel insight into disease mechanisms and help to design better therapies for these disorders.
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Abbreviations
- AD:
-
Alzheimer's disease
- Aβ:
-
amyloid β-peptide
- ALS:
-
amyotrophic lateral sclerosis
- ASK1:
-
apoptosis signal-regulating kinase-1
- ER:
-
endoplasmic reticulum
- FAD:
-
familial AD
- FALS:
-
familial ALS
- GRP78:
-
78 Kda glucose-regulated protein
- HD:
-
Huntington's disease
- IP3-R:
-
inositol 1,4,5-triphosphate receptor
- JNK:
-
c-Jun NH2-terminal kinase
- LSD:
-
lysosomal storage diseases
- NCL:
-
neuronal ceroid lipofuscinoses
- Pael-R:
-
Pael receptor
- PD:
-
Parkinson's disease
- PMD:
-
Pelizaeus-Merzbacher disease
- polyQ:
-
polyglutamine
- PS-1:
-
presenilin-1
- PS-2:
-
presenilin-2
- PrP:
-
prion protein
- RING:
-
really interesting new gene
- SCA:
-
spinocerebellar ataxia
- SOD1:
-
Cu/Zn superoxide dismutase
- TSE:
-
transmissible spongiform encephalopathy
- UCHL-1:
-
ubiquitin carboxyl-terminal hydrolase-1
- UPS:
-
ubiquitin proteasome system
- UPR:
-
unfolded protein response
- 6-OHDA:
-
6-hydroxydopamine
References
Paschen W and Frandsen A (2001) Endoplasmic reticulum dysfunction a common denominator for cell injury in acute and degenerative diseases of the brain? J. Neurochem. 79: 719–725
Breckenridge DG, Germain M, Mathai JP, Nguyen M and Shore GC (2003) Regulation of apoptosis by endoplasmic reticulum pathways. Oncogene 22: 8608–8618
Rao RV, Ellerby HM and Bredesen DE (2004) Coupling endoplasmic reticulum stress to the cell death program. Cell Death Differentiation 11: 372–380
Ciechanover A and Brundin P (2003) The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg. Neuron 40: 427–446
Imai Y, Soda M, Inoue H, Hattori N, Mizuno Y and Takahashi R (2001) An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 105: 891–902
Korhonen L and Lindholm D (2004) The ubiquitin proteasome system in synaptic and axonal degeneration: a new twist to an old cycle. J Cell Biol. 165: 27–30
Soto C (2003) Unfolding the role of protein misfolding in neurodegenerative diseases. Nat. Rev. Neurosci. 4: 49–60
Bence NF, Sampat RM and Kopito RR (2001) Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292: 1552–1555
Nishitoh H, Matsuzawa A, Tobiume K, Saegusa K, Takeda K, Inoue K, Hori S, Kakizuka A and Ichijo H (2002) ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev. 16: 1345–1355
Degterev A, Boyce M and Yuan J (2003) A decade of caspases. Oncogene 22: 8543–8567
Verkhratsky A (2005) Physiology and pathophysiology of the calcium store in the endoplasmic reticulum of neurons. Physiol. Rev. 85: 201–279
Mattson MP (2000) Apoptosis in neurodegenerative disorders. Nature Rev. Mol. Cell Biol. 1: 120–129
Yuan J, Lipinski M and Degterev A (2003) Diversity in the mechanisms of neuronal cell death. Neuron 40: 401–413
Danial NN and Korsmeyer SJ (2004) Cell death: critical control points. Cell 116: 205–219
Wyss-Coray T and Mucke L (2002) Inflammation in neurodegenerative disease – a double-edged sword. Neuron 35: 419–432
Germain M, Mathai JP and Shore GC (2002) BH-3-only BIK functions at the endoplasmic reticulum to stimulate cytochrome c release from mitochondria. J. Biol. Chem. 277: 18053–18060
Mund T, Gewies A, Schoenfeld N, Bauer MK and Grimm S (2003) Spike, a novel BH3-only protein, regulates apoptosis at the endoplasmic reticulum. FASEB J. 17: 696–698
Morishima N, Nakanishi K, Tsuchiya K, Shibata T and Seiwa E (2004) Translocation of Bim to the endoplasmic reticulum (ER) mediates ER stress signaling for activation of caspase-12 during ER stress-induced apoptosis. J. Biol. Chem. 279: 50375–50381
Chen R, Valencia I, Zhong F, McColl KS, Roderick HL, Bootman MD, Berridge MJ, Conway SJ, Holmes AB, Mignery GA, Velez P and Distelhorst CW (2004) Bcl-2 functionally interacts with inositol 1,4,5-trisphosphate receptors to regulate calcium release from the ER in response to inositol 1,4,5-trisphosphate. J. Cell Biol. 166: 193–203
Simmen T, Aslan JE, Blagoveshchenskaya AD, Thomas L, Wan L, Xiang Y, Feliciangeli SF, Hung CH, Crump CM and Thomas G (2005) PACS-2 controls endoplasmic reticulum-mitochondria communication and Bid-mediated apoptosis. EMBO J. 24: 717–729
Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA and Yuan J (2000) Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403: 98–103
Rao RV, Castro-Obregon S, Frankowski H, Schuler M, Stoka V, Del Rio G, Bredesen DE and Ellerby HM (2002) Coupling endoplasmic reticulum stress to the cell death program. An Apaf-1-independent intrinsic pathway. J. Biol. Chem. 277: 21836–21842
Morishima N, Nakanishi K, Takenouchi H, Shibata T and Yasuhiko Y (2002) An endoplasmic reticulum stress-specific caspase cascade in apoptosis. Cytochrome c-independent activation of caspase-9 by caspase-12. J. Biol. Chem. 277: 34287–34294
Obeng EA and Boise LH (2005) Caspase-12 and caspase-4 are not required for caspase-dependent endoplasmic reticulum stress-induced apoptosis. J. Biol. Chem. 280: 29578–29587
Hitomi J, Katayama T, Eguchi Y, Kudo T, Taniguchi M, Koyama Y, Manabe T, Yamagishi S, Bando Y, Imaizumi K, Tsujimoto Y and Tohyama M. (2004) Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Abeta-induced cell death. J. Cell Biol. 165: 347–356
Selkoe DJ (2001) Alzheimer's disease: genes, proteins, and therapy. Physiol. Rev. 81: 741–766
Korhonen L, Hansson I, Kukkonen JP, Brannvall K, Kobayashi M, Takamatsu K and Lindholm D (2005) Hippocalcin protects against caspase-12-induced and age-dependent neuronal degeneration. Mol. Cell Neurosci. 28: 85–95
Shimoke K, Utsumi T, Kishi S, Nishimura M, Sasaya H, Kudo M and Ikeuchi T (2004) Prevention of endoplasmic reticulum stress-induced cell death by brain-derived neurotrophic factor in cultured cerebral cortical neurons. Brain Res. 1028: 105–111
Healy DG, Abou-Sleiman PM and Wood NW (2004) PINK, PANK, or PARK? A clinicians’ guide to familial parkinsonism. Lancet Neurol. 3: 652–662
Greenamyre JT and Hastings TG (2004) Parkinson's—divergent causes, convergent mechanisms. Science 304: 1120–1122
Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV and Greenamyre JT (2000) Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat. Neurosci. 3: 1301–1306
Shen J (2004) Protein kinases linked to the pathogenesis of Parkinson's disease. Neuron 44: 575–577
Imai Y and Takahashi R (2004) How do Parkin mutations result in neurodegeneration? Curr. Opin. Neurobiol. 14: 384–389
Kalia SK, Lee S, Smith PD, Liu L, Crocker SJ, Thorarinsdottir TE, Glover JR, Fon EA, Park DS and Lozano AM (2004) BAG5 inhibits parkin and enhances dopaminergic neuron degeneration. Neuron 44: 931–945
Murakami T, Shoji M, Imai Y, Inoue H, Kawarabayashi T, Matsubara E, Harigaya Y, Sasaki A, Takahashi R and Abe K (2004) Pael-R is accumulated in Lewy bodies of Parkinson's disease. Ann. Neurol. 55: 439–442
Holtz WA and O’Malley KL (2003) Parkinsonian mimetics induce aspects of unfolded protein response in death of dopaminergic neurons. J. Biol. Chem. 278: 19367–19377
Ryu EJ, Harding HP, Angelastro JM, Vitolo OV, Ron D and Greene LA (2002) Endoplasmic reticulum stress and the unfolded protein response in cellular models of Parkinson's disease. J. Neurosci. 22: 10690–10698
Wilquet V and De Strooper B (2004) Amyloid-beta precursor protein processing in neurodegeneration. Curr. Opin. Neurobiol. 14: 582–584
LaFerla F (2002) Calcium dyshomeostasis and intracellular signalling in Alzheimer's disease. Nat. Rev. Neurosci. 3: 862–872
Kadowaki H, Nishitoh H, Urano F, Sadamitsu C, Matsuzawa A, Takeda K, Masutani H, Yodoi J, Urano Y, Nagano T and Ichijo H (2005) Amyloid beta induces neuronal cell death through ROS-mediated ASK1 activation. Cell Death Differentiation 12: 19–24
Katayama T, Imaizumi K, Manabe T, Hitomi J, Kudo T and Tohyama M (2004) Induction of neuronal death by ER stress in Alzheimer's disease. J. Chem. Neuroanat. 28: 67–78
Suh YH and Checler F (2002) Amyloid precursor protein, presenilins, and alpha-synuclein: molecular pathogenesis and pharmacological applications in Alzheimer's disease. Pharmacol. Rev. 54: 469–525
Demuro A, Mina E, Kayed R, Milton SC, Parker I and Glabe CG (2005) Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers. J. Biol. Chem. 280: 17294–17300
Hoozemans JJ, Veerhuis R, Van Haastert ES, Rozemuller JM, Baas F, Eikelenboom P and Scheper W (2005) The unfolded protein response is activated in Alzheimer's disease. Acta Neuropathol. 110: 165–172
Bruijn LI, Miller TM and Cleveland DW (2004) Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annu. Rev. Neurosci. 27: 723–749
Inoue H, Tsukita K, Iwasato T, Suzuki Y, Tomioka M, Tateno M, Nagao M, Kawata A, Saido TC, Miura M, Misawa H, Itohara S and Takahashi R (2003) The crucial role of caspase-9 in the disease progression of a transgenic ALS mouse model. EMBO J. 22: 6665–6674
Pasinelli P, Belford ME, Lennon N, Bacskai BJ, Hyman BT, Trotti D and Brown Jr RH (2004) Amyotrophic lateral sclerosis-associated SOD1 mutant proteins bind and aggregate with Bcl-2 in spinal cord mitochondria. Neuron 43: 19–30
Niwa J, Ishigaki S, Hishikawa N, Yamamoto M, Doyu M, Murata S, Tanaka K, Taniguchi N and Sobue G (2002) Dorfin ubiquitylates mutant SOD1 and prevents mutant SOD1-mediated neurotoxicity. J. Biol. Chem. 277: 36793–36798
Wootz H, Hansson I, Korhonen L, Napankangas U and Lindholm D (2004) Caspase-12 cleavage and increased oxidative stress during motoneuron degeneration in transgenic mouse model of ALS. Biochem. Biophys. Res. Commun. 322: 281–286
Nakagawa T and Yuan J (2000) Cross-talk between two cysteine protease families. Activation of caspase-12 by calpain in apoptosis. J. Cell Biol. 150: 887–894
Kang SJ, Sanchez I, Jing N and Yuan J (2003) Dissociation between neurodegeneration and caspase-11-mediated activation of caspase-1 and caspase-3 in a mouse model of amyotrophic lateral sclerosis. J. Neurosci. 23: 5455–5560
Tobisawa S, Hozumi Y, Arawaka S, Koyama S, Wada M, Nagai M, Aoki M, Itoyama Y, Goto K and Kato T (2003) Mutant SOD1 linked to familial amyotrophic lateral sclerosis, but not wild-type SOD1, induces ER stress in COS7 cells and transgenic mice. Biochem. Biophys. Res. Commun. 303: 496–503
Prusiner SB (1998) Prions. Proc. Natl. Acad. Sci. USA 95: 13363–13383
Soto C and Castilla J (2004) The controversial protein-only hypothesis of prion propagation. Nat. Med. 10: S63–S67
Hetz C, Russelakis-Carneiro M, Maundrell K, Castilla J and Soto C (2003) Caspase-12 and endoplasmic reticulum stress mediate neurotoxicity of pathological prion protein. EMBO J. 22: 5435–5445
Hetz C, Russelakis-Carneiro M, Walchli S, Carboni S, Vial-Knecht E, Maundrell K, Castilla J and Soto C (2005) The disulfide isomerase Grp58 is a protective factor against prion neurotoxicity. J. Neurosci. 25: 2793–2802
Zoghbi HY and Orr HT (2000) Glutamine repeats and neurodegeneration. Annu. Rev. Neurosci. 23: 217–247
Lipinski MM and Yuan J (2004) Mechanisms of cell death in polyglutamine expansion diseases. Curr. Opin. Pharmacol. 4: 85–90
Tang TS, Tu H, Chan EY, Maximov A, Wang Z, Wellington CL, Hayden MR and Bezprozvanny I (2003) Huntingtin and huntingtin-associated protein 1 influence neuronal calcium signaling mediated by inositol-(1,4,5) triphosphate receptor type 1. Neuron 39: 227–239
Thomas M, Yu Z, Dadgar N, Varambally S, Yu J, Chinnaiyan AM and Lieberman AP (2005) The unfolded protein response modulates toxicity of the expanded glutamine androgen receptor. J. Biol. Chem. 280: 21264–21271
Kouroku Y, Fujita E, Jimbo A, Kikuchi T, Yamagata T, Momoi MY, Kominami E, Kuida K, Sakamaki K, Yonehara S and Momoi T (2002) Polyglutamine aggregates stimulate ER stress signals and caspase-12 activation. Hum. Mol. Genet. 11: 1505–1515
Tessitore A, del P Martin M, Sano R, Ma Y, Mann L, Ingrassia A, Laywell ED, Steindler DA, Hendershot LM and d’Azzo A (2004) GM1-ganglioside-mediated activation of the unfolded protein response causes neuronal death in a neurodegenerative gangliosidosis. Mol. Cell 15: 753–766
Pelled D, Lloyd-Evans E, Riebeling C, Jeyakumar M, Platt FM and Futerman AH (2003) Inhibition of calcium uptake via the sarco/endoplasmic reticulum Ca2+-ATPase in a mouse model of Sandhoff disease and prevention by treatment with N-butyldeoxynojirimycin. J. Biol. Chem. 278: 29496–29501
Southwood CM, Garbern J, Jiang W and Gow A (2002) The unfolded protein response modulates disease severity in Pelizaeus-Merzbacher disease. Neuron 36: 585–596
Lonka L, Kyttala A, Ranta S, Jalanko A and Lehesjoki AE (2000) The neuronal ceroid lipofuscinosis CLN8 membrane protein is a resident of the endoplasmic reticulum. Hum. Mol. Genet. 9: 1691–1697
Hayashi T, Saito A, Okuno S, Ferrand-Drake M, Dodd RL and Chan PH (2005) Damage to the endoplasmic reticulum and activation of apoptotic machinery by oxidative stress in ischemic neurons. J. Cereb. Blood Flow Metab. 25: 41–53
Tajiri S, Oyadomari S, Yano S, Morioka M, Gotoh T, Hamada JI, Ushio Y and Mori M (2004) Ischemia-induced neuronal cell death is mediated by the endoplasmic reticulum stress pathway involving CHOP. Cell Death Differ. 11: 403–415
Larner SF, Hayes RL, McKinsey DM, Pike BR and Wang KK (2004) Increased expression and processing of caspase-12 after traumatic brain injury in rats. J. Neurochem. 88: 78–90
Bando Y, Katayama T, Kasai K, Taniguchi M, Tamatani M and Tohyama M (2003) GRP94 (94 kDa glucose-regulated protein) suppresses ischemic neuronal cell death against ischemia/reperfusion injury. Eur. J. Neurosci. 18: 829–840
Tamatani M, Matsuyama T, Yamaguchi A, Mitsuda N, Tsukamoto Y, Taniguchi M, Che YH, Ozawa K, Hori O, Nishimura H, Yamashita A, Okabe M, Yanagi H, Stern DM, Ogawa S and Tohyama M (2001) ORP150 protects against hypoxia/ischemia-induced neuronal death. Nat. Med. 7: 317–323
Acknowledgements
We apologize to our colleagues whose eminent work we were unable to cite due to space limitation. Supported by Uppsala University, Minerva Foundation, Björklund Foundation, Sigrid Juselius, Arvo and Lea Ylppö Foundation and Finnish Academy.
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Lindholm, D., Wootz, H. & Korhonen, L. ER stress and neurodegenerative diseases. Cell Death Differ 13, 385–392 (2006). https://doi.org/10.1038/sj.cdd.4401778
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DOI: https://doi.org/10.1038/sj.cdd.4401778
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