Unfolded protein response markers Grp78 and eIF2alpha are upregulated with increasing alpha-synuclein levels in Lewy body disease
Jazyk angličtina Země Anglie, Velká Británie Médium print
Typ dokumentu časopisecké články
Grantová podpora
PF-IMP-941400
Parkinson's Foundation
MH CZ-DRO (FNOl, 00098892)
Ministry of Health, Czech Republic - conceptual development of research organization
IGA_LF_2024_010
Palacky University Olomouc
IGA_LF_2024_021
Palacky University Olomouc
G-1806
Parkinson's UK - United Kingdom
Weston Brain Institute
MJFF-019580
Michael J. Fox Foundation
NIHR Oxford Biomedical Research Centre
PubMed
39036837
DOI
10.1111/nan.12999
Knihovny.cz E-zdroje
- Klíčová slova
- ER stress, Lewy body disease, Parkinson's disease, alpha‐synuclein, unfolded protein response,
- MeSH
- alfa-synuklein * metabolismus MeSH
- biologické markery metabolismus MeSH
- chaperon endoplazmatického retikula BiP * metabolismus MeSH
- demence s Lewyho tělísky * patologie metabolismus MeSH
- eukaryotický iniciační faktor 2 * metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- mozek metabolismus patologie MeSH
- neurotrofní faktory metabolismus MeSH
- proteiny tepelného šoku * metabolismus MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- signální dráha UPR * fyziologie MeSH
- stres endoplazmatického retikula fyziologie MeSH
- upregulace * MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- alfa-synuklein * MeSH
- biologické markery MeSH
- chaperon endoplazmatického retikula BiP * MeSH
- EIF2S1 protein, human MeSH Prohlížeč
- eukaryotický iniciační faktor 2 * MeSH
- HSPA5 protein, human MeSH Prohlížeč
- MANF protein, human MeSH Prohlížeč
- neurotrofní faktory MeSH
- proteiny tepelného šoku * MeSH
- SNCA protein, human MeSH Prohlížeč
AIMS: Endoplasmic reticulum stress followed by the unfolded protein response is one of the cellular mechanisms contributing to the progression of α-synuclein pathology in Parkinson's disease and other Lewy body diseases. We aimed to investigate the activation of endoplasmic reticulum stress and its correlation with α-synuclein pathology in human post-mortem brain tissue. METHODS: We analysed brain tissue from 45 subjects-14 symptomatic patients with Lewy body disease, 19 subjects with incidental Lewy body disease, and 12 healthy controls. The analysed brain regions included the medulla, pons, midbrain, striatum, amygdala and entorhinal, temporal, frontal and occipital cortex. We analysed activation of endoplasmic reticulum stress via levels of the unfolded protein response-related proteins (Grp78, eIF2α) and endoplasmic reticulum stress-regulating neurotrophic factors (MANF, CDNF). RESULTS: We showed that regional levels of two endoplasmic reticulum-localised neurotrophic factors, MANF and CDNF, did not change in response to accumulating α-synuclein pathology. The concentration of MANF negatively correlated with age in specific regions. eIF2α was upregulated in the striatum of Lewy body disease patients and correlated with increased α-synuclein levels. We found the upregulation of chaperone Grp78 in the amygdala and nigral dopaminergic neurons of Lewy body disease patients. Grp78 levels in the amygdala strongly correlated with soluble α-synuclein levels. CONCLUSIONS: Our data suggest a strong but regionally specific change in Grp78 and eIF2α levels, which positively correlates with soluble α-synuclein levels. Additionally, MANF levels decreased in dopaminergic neurons in the substantia nigra. Our research suggests that endoplasmic reticulum stress activation is not associated with Lewy pathology but rather with soluble α-synuclein concentration and disease progression.
Mammalian Genetics Unit MRC Harwell Institute Harwell Science and Innovation Campus Didcot UK
Nuffield Department of Clinical Neuroscience University of Oxford Oxford UK
Zobrazit více v PubMed
Dickson DW, Braak H, Duda JE, et al. Neuropathological assessment of Parkinson's disease: refining the diagnostic criteria. Lancet Neurol. 2009;8(12):1150‐1157. doi:10.1016/S1474‐4422(09)70238‐8 Retraction in: Lancet Neurol. 2010 Jan;9(1):29
Shahmoradian SH, Lewis AJ, Genoud C, et al. Lewy pathology in Parkinson's disease consists of crowded organelles and lipid membranes. Nat Neurosci. 2019;22(7):1099‐1109. doi:10.1038/s41593‐019‐0423‐2
Wakabayashi K, Tanji K, Odagiri S, Miki Y, Mori F, Takahashi H. The Lewy body in Parkinson's disease and related neurodegenerative disorders. Mol Neurobiol. 2013;47(2):495‐508. doi:10.1007/s12035‐012‐8280‐y
Braak H, Del Tredici K, Rüb U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. 2003;24(2):197‐211. doi:10.1016/s0197‐4580(02)00065‐9
Parkkinen L, Pirttilä T, Alafuzoff I. Applicability of current staging/categorization of alpha‐synuclein pathology and their clinical relevance. Acta Neuropathol. 2008;115(4):399‐407. doi:10.1007/s00401‐008‐0346‐6
Parkkinen L, O'Sullivan SS, Collins C, et al. Disentangling the relationship between lewy bodies and nigral neuronal loss in Parkinson's disease. J Parkinsons Dis. 2011;1(3):277‐286. doi:10.3233/JPD‐2011‐11046
Mercado G, Valdés P, Hetz C. An ERcentric view of Parkinson's disease. Trends Mol Med. 2013;19(3):165‐175. doi:10.1016/j.molmed.2012.12.005
Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science. 2011;334(6059):1081‐1086. doi:10.1126/science.1209038
Hetz C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol. 2012;13(2):89‐102. Published 2012 Jan 18. doi:10.1038/nrm3270
Acosta‐Alvear D, Zhou Y, Blais A, et al. XBP1 controls diverse cell type‐ and condition‐specific transcriptional regulatory networks. Mol Cell. 2007;27(1):53‐66. doi:10.1016/j.molcel.2007.06.011
Hetz C, Saxena S. ER stress and the unfolded protein response in neurodegeneration. Nat Rev Neurol. 2017;13(8):477‐491. doi:10.1038/nrneurol.2017.99
Urra H, Dufey E, Lisbona F, Rojas‐Rivera D, Hetz C. When ER stress reaches a dead end. Biochim Biophys Acta. 2013;1833(12):3507‐3517. doi:10.1016/j.bbamcr.2013.07.024
Hu P, Han Z, Couvillon AD, Kaufman RJ, Exton JH. Autocrine tumor necrosis factor alpha links endoplasmic reticulum stress to the membrane death receptor pathway through IRE1alpha‐mediated NF‐kappaB activation and down‐regulation of TRAF2 expression. Mol Cell Biol. 2006;26(8):3071‐3084. doi:10.1128/MCB.26.8.3071‐3084.2006
Lindholm P, Saarma M. Novel CDNF/MANF family of neurotrophic factors. Dev Neurobiol. 2010;70(5):360‐371. doi:10.1002/dneu.20760
Lindholm P, Voutilainen MH, Laurén J, et al. Novel neurotrophic factor CDNF protects and rescues midbrain dopamine neurons in vivo. Nature. 2007;448(7149):73‐77. doi:10.1038/nature05957
Voutilainen MH, Bäck S, Peränen J, et al. Chronic infusion of CDNF prevents 6‐OHDA‐induced deficits in a rat model of Parkinson's disease. Exp Neurol. 2011;228(1):99‐108. doi:10.1016/j.expneurol.2010.12.013
Arancibia D, Zamorano P, Andrés ME. CDNF induces the adaptive unfolded protein response and attenuates endoplasmic reticulum stress‐induced cell death. Biochim Biophys Acta Mol Cell Res. 2018;1865(11 Pt A):1579‐1589. doi:10.1016/j.bbamcr.2018.08.012
Latge C, Cabral KM, de Oliveira GA, et al. The solution structure and dynamics of full‐length human cerebral dopamine neurotrophic factor and its neuroprotective role against α‐Synuclein oligomers. J Biol Chem. 2015;290(33):20527‐20540. doi:10.1074/jbc.M115.662254
Albert K, Raymundo DP, Panhelainen A, et al. Cerebral dopamine neurotrophic factor reduces α‐synuclein aggregation and propagation and alleviates behavioral alterations in vivo. Mol Ther. 2021;29(9):2821‐2840. doi:10.1016/j.ymthe.2021.04.035
Mizobuchi N, Hoseki J, Kubota H, et al. ARMET is a soluble ER protein induced by the unfolded protein response via ERSE‐II element. Cell Struct Funct. 2007;32(1):41‐50. doi:10.1247/csf.07001
Tadimalla A, Belmont PJ, Thuerauf DJ, et al. Mesencephalic astrocyte‐derived neurotrophic factor is an ischemia‐inducible secreted endoplasmic reticulum stress response protein in the heart. Circ Res. 2008;103(11):1249‐1258. doi:10.1161/CIRCRESAHA.108.180679
Lindholm P, Peränen J, Andressoo JO, et al. MANF is widely expressed in mammalian tissues and differently regulated after ischemic and epileptic insults in rodent brain. Mol Cell Neurosci. 2008;39(3):356‐371. doi:10.1016/j.mcn.2008.07.016
Henderson MJ, Richie CT, Airavaara M, Wang Y, Harvey BK. Mesencephalic astrocyte‐derived neurotrophic factor (MANF) secretion and cell surface binding are modulated by KDEL receptors. J Biol Chem. 2013;288(6):4209‐4225. doi:10.1074/jbc.M112.400648
Eesmaa A, Yu LY, Göös H, et al. The cytoprotective protein MANF promotes neuronal survival independently from its role as a GRP78 cofactor. J Biol Chem. 2021;296:100295. doi:10.1016/j.jbc.2021.100295
Ryu EJ, Harding HP, Angelastro JM, Vitolo OV, Ron D, Greene LA. Endoplasmic reticulum stress and the unfolded protein response in cellular models of Parkinson's disease. J Neurosci. 2002;22(24):10690‐10698. doi:10.1523/JNEUROSCI.22‐24‐10690.2002
Smith WW, Jiang H, Pei Z, et al. Endoplasmic reticulum stress and mitochondrial cell death pathways mediate A53T mutant alpha‐synuclein‐induced toxicity. Hum Mol Genet. 2005;14(24):3801‐3811. doi:10.1093/hmg/ddi396
Mercado G, Castillo V, Soto P, Sidhu A. ER stress and Parkinson's disease: pathological inputs that converge into the secretory pathway. Brain Res. 2016;1648(Pt B):626‐632. doi:10.1016/j.brainres.2016.04.042
Heman‐Ackah SM, Manzano R, Hoozemans JJM, et al. Alpha‐synuclein induces the unfolded protein response in Parkinson's disease SNCA triplication iPSC‐derived neurons. Hum Mol Genet. 2017;26(22):4441‐4450. doi:10.1093/hmg/ddx331
Bellucci A, Navarria L, Zaltieri M, et al. Induction of the unfolded protein response by α‐synuclein in experimental models of Parkinson's disease. J Neurochem. 2011;116(4):588‐605. doi:10.1111/j.1471‐4159.2010.07143.x
Colla E, Coune P, Liu Y, et al. Endoplasmic reticulum stress is important for the manifestations of α‐synucleinopathy in vivo. J Neurosci. 2012;32(10):3306‐3320. doi:10.1523/JNEUROSCI.5367‐11.2012
Cooper AA, Gitler AD, Cashikar A, et al. Alpha‐synuclein blocks ER‐Golgi traffic and Rab1 rescues neuron loss in Parkinson's models. Science. 2006;313(5785):324‐328. doi:10.1126/science.1129462
Sugeno N, Takeda A, Hasegawa T, et al. Serine 129 phosphorylation of alpha‐synuclein induces unfolded protein response‐mediated cell death. J Biol Chem. 2008;283(34):23179‐23188. doi:10.1074/jbc.M802223200
Credle JJ, Forcelli PA, Delannoy M, et al. α‐Synuclein‐mediated inhibition of ATF6 processing into COPII vesicles disrupts UPR signaling in Parkinson's disease. Neurobiol Dis. 2015;76:112‐125. doi:10.1016/j.nbd.2015.02.005
Hoozemans JJ, van Haastert ES, Eikelenboom P, de Vos RA, Rozemuller JM, Scheper W. Activation of the unfolded protein response in Parkinson's disease. Biochem Biophys Res Commun. 2007;354(3):707‐711. doi:10.1016/j.bbrc.2007.01.043
Galli E, Härkönen T, Sainio MT, et al. Increased circulating concentrations of mesencephalic astrocyte‐derived neurotrophic factor in children with type 1 diabetes. Sci Rep. 2016;6(1):29058. Published 2016 Jun 30. doi:10.1038/srep29058
Galli E, Lindholm P, Kontturi LS, Saarma M, Urtti A, Yliperttula M. Characterization of CDNF‐secreting ARPE‐19 cell clones for encapsulated cell therapy. Cell Transplant. 2019;28(4):413‐424. doi:10.1177/0963689719827943
Diner I, Nguyen T, Seyfried NT. Enrichment of detergent‐insoluble protein aggregates from human postmortem brain. J vis Exp. 2017;(128):55835. Published 2017 Oct 24. doi:10.3791/55835
Schweighauser M, Shi Y, Tarutani A, et al. Structures of α‐synuclein filaments from multiple system atrophy. Nature. 2020;585(7825):464‐469. doi:10.1038/s41586‐020‐2317‐6
Desjardins P, Conklin D. NanoDrop microvolume quantitation of nucleic acids. J vis Exp. 2010;(45):2565. Published 2010 Nov 22. doi:10.3791/2565
Sarcinelli C, Dragic H, Piecyk M, et al. ATF4‐dependent NRF2 transcriptional regulation promotes antioxidant protection during endoplasmic reticulum stress. Cancers (Basel). 2020;12. Published 2020 Mar 1(3):569. doi:10.3390/cancers12030569
Sousa‐Victor P, Neves J, Cedron‐Craft W, et al. MANF regulates metabolic and immune homeostasis in ageing and protects against liver damage. Nat Metab. 2019;1(2):276‐290. doi:10.1038/s42255‐018‐0023‐6
Baek JH, Mamula D, Tingstam B, Pereira M, He Y, Svenningsson P. GRP78 level is altered in the brain, but not in plasma or cerebrospinal fluid in Parkinson's disease patients. Front Neurosci. 2019;13:697. Published 2019 Jul 5. doi:10.3389/fnins.2019.00697
Nemani VM, Lu W, Berge V, et al. Increased expression of alpha‐synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron. 2010;65(1):66‐79. doi:10.1016/j.neuron.2009.12.023
Colla E. Linking the endoplasmic reticulum to Parkinson's disease and alpha‐synucleinopathy. Front Neurosci. 2019;13:560. Published 2019 May 29. doi:10.3389/fnins.2019.00560
Iacono D, Geraci‐Erck M, Rabin ML, et al. Parkinson disease and incidental Lewy body disease: just a question of time? Neurology. 2015;85(19):1670‐1679. doi:10.1212/WNL.0000000000002102
Mercado G, Castillo V, Soto P, et al. Targeting PERK signaling with the small molecule GSK2606414 prevents neurodegeneration in a model of Parkinson's disease. Neurobiol Dis. 2018;112:136‐148. doi:10.1016/j.nbd.2018.01.004
Halliday M, Radford H, Sekine Y, et al. Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity. Cell Death Dis. 2015;6(3):e1672. Published 2015 Mar 5. doi:10.1038/cddis.2015.49
Halliday M, Radford H, Zents KAM, et al. Repurposed drugs targeting eIF2α‐P‐mediated translational repression prevent neurodegeneration in mice. Brain. 2017;140(6):1768‐1783. doi:10.1093/brain/awx074
Herantis Pharma. CDNF phase I 12‐month topline results: safety, UPDRS and DAT PET data. 2020. https://herantis.com/wp-content/uploads/2020/09/200915-CDNF-Webinar_FINAL.pdf. Accessed Nov 3, 2020.