Login Register Cart 0
Generic placeholder image

CNS & Neurological Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5273
ISSN (Online): 1996-3181

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Ablation of Shank1 Protects against 6-OHDA-induced Cytotoxicity via PRDX3-mediated Inhibition of ER Stress in SN4741 Cells

Author(s): Ye-Ping Xu, Jing Zhang, Xue Mei, Yan Wu, Wei Jiao, Yu-Hai Wang* and Ai-Qin Zhang*

Volume 23, Issue 3, 2024

Published on: 16 March, 2023

Page: [402 - 410] Pages: 9

DOI: 10.2174/1871527322666230216124156

Price: $65

conference banner
Abstract

Background: Postsynaptic density (PSD) is an electron-dense structure that contains various scaffolding and signaling proteins. Shank1 is a master regulator of the synaptic scaffold located at glutamatergic synapses, and has been proposed to be involved in multiple neurological disorders.

Methods: In this study, we investigated the role of shank1 in an in vitro Parkinson’s disease (PD) model mimicked by 6-OHDA treatment in neuronal SN4741 cells. The expression of related molecules was detected by western blot and immunostaining.

Results: We found that 6-OHDA significantly increased the mRNA and protein levels of shank1 in SN4741 cells, but the subcellular distribution was not altered. Knockdown of shank1 via small interfering RNA (siRNA) protected against 6-OHDA treatment, as evidenced by reduced lactate dehydrogenase (LDH) release and decreased apoptosis. The results of RT-PCR and western blot showed that knockdown of shank1 markedly inhibited the activation of endoplasmic reticulum (ER) stress associated factors after 6-OHDA exposure. In addition, the downregulation of shank1 obviously increased the expression of PRDX3, which was accompanied by the preservation of mitochondrial function. Mechanically, downregulation of PRDX3 via siRNA partially prevented the shank1 knockdowninduced protection against 6-OHDA in SN4741 cells.

Conclusion: In summary, the present study has provided the first evidence that the knockdown of shank1 protects against 6-OHDA-induced ER stress and mitochondrial dysfunction through activating the PRDX3 pathway.

« Previous
Graphical Abstract

[1]
Crowley EK, Nolan YM, Sullivan AM. Exercise as a therapeutic intervention for motor and non-motor symptoms in Parkinson’s disease: Evidence from rodent models. Prog Neurobiol 2019; 172: 2-22.
[http://dx.doi.org/10.1016/j.pneurobio.2018.11.003] [PMID: 30481560]
[2]
Rana AQ, Ahmed US, Chaudry ZM, Vasan S. Parkinson’s disease: A review of non-motor symptoms. Expert Rev Neurother 2015; 15(5): 549-62.
[http://dx.doi.org/10.1586/14737175.2015.1038244] [PMID: 25936847]
[3]
Dawson TM, Dawson VL. Neuroprotective and neurorestorative strategies for Parkinson’s disease. Nat Neurosci 2002; 5(S11): 1058-61.
[http://dx.doi.org/10.1038/nn941] [PMID: 12403986]
[4]
Greenamyre JT, Hastings TG. Biomedicine. Parkinson’s-divergent causes, convergent mechanisms. Science 2004; 304(5674): 1120-2.
[http://dx.doi.org/10.1126/science.1098966] [PMID: 15155938]
[5]
Dauer W, Przedborski S. Parkinson’s Disease. Neuron 2003; 39(6): 889-909.
[http://dx.doi.org/10.1016/S0896-6273(03)00568-3] [PMID: 12971891]
[6]
Mossa A, Giona F, Pagno J, et al. SHANK genes in autism: Defining therapeutic targets. Prog Neuropsychopharmacol Biol Psychiat 2018; 84(pt B): 416-23.
[http://dx.doi.org/10.1016/j.pnpbp.2017.11.019]
[7]
Shi R, Redman P, Ghose D, et al. Shank proteins differentially regulate synaptic transmission. ENeuro 2017; 4(6): 0163-15.
[http://dx.doi.org/10.1523/ENEURO.0163-15.2017] [PMID: 29250591]
[8]
Sala C, Piëch V, Wilson NR, Passafaro M, Liu G, Sheng M. Regulation of dendritic spine morphology and synaptic function by Shank and Homer. Neuron 2001; 31(1): 115-30.
[http://dx.doi.org/10.1016/S0896-6273(01)00339-7] [PMID: 11498055]
[9]
Lim S, Naisbitt S, Yoon J, et al. Characterization of the shank family of synaptic proteins. Multiple genes, alternative splicing, and differential expression in brain and development. J Biol Chem 1999; 274(41): 29510-8.
[http://dx.doi.org/10.1074/jbc.274.41.29510] [PMID: 10506216]
[10]
Roussignol G, Ango F, Romorini S, et al. Shank expression is sufficient to induce functional dendritic spine synapses in aspiny neurons. J Neurosci 2005; 25(14): 3560-70.
[http://dx.doi.org/10.1523/JNEUROSCI.4354-04.2005] [PMID: 15814786]
[11]
Mao W, Watanabe T, Cho S, et al. Shank1 regulates excitatory synaptic transmission in mouse hippocampal parvalbumin-expressing inhibitory interneurons. Eur J Neurosci 2015; 41(8): 1025-35.
[http://dx.doi.org/10.1111/ejn.12877] [PMID: 25816842]
[12]
Gardoni F, Di Luca M. Targeting glutamatergic synapses in Parkinson’s disease. Curr Opin Pharmacol 2015; 20: 24-8.
[http://dx.doi.org/10.1016/j.coph.2014.10.011] [PMID: 25462288]
[13]
Zhang Z, Zhang S, Fu P, et al. Roles of glutamate receptors in Parkinson’s disease. Int J Mol Sci 2019; 20(18): 4391.
[http://dx.doi.org/10.3390/ijms20184391] [PMID: 31500132]
[14]
Chen T, Yang Y, Luo P, et al. Homer1 knockdown protects dopamine neurons through regulating calcium homeostasis in an in vitro model of Parkinson’s disease. Cell Signal 2013; 25(12): 2863-70.
[http://dx.doi.org/10.1016/j.cellsig.2013.09.004] [PMID: 24036210]
[15]
Lindgren HS, Lelos MJ, Dunnett SB. Do α-synuclein vector injections provide a better model of Parkinson’s disease than the classic 6-hydroxydopamine model? Exp Neurol 2012; 237(1): 36-42.
[http://dx.doi.org/10.1016/j.expneurol.2012.05.022] [PMID: 22727767]
[16]
Dou G, Sreekumar PG, Spee C, et al. Deficiency of αB crystallin augments ER stress-induced apoptosis by enhancing mitochondrial dysfunction. Free Radic Biol Med 2012; 53(5): 1111-22.
[http://dx.doi.org/10.1016/j.freeradbiomed.2012.06.042] [PMID: 22781655]
[17]
Qu J, Wu Y, Zhang T, Qiu Y, Ding Z, Zha D. Sirt3 confers protection against acrolein-induced oxidative stress in cochlear nucleus neurons. Neurochem Int 2018; 114: 1-9.
[http://dx.doi.org/10.1016/j.neuint.2017.12.004] [PMID: 29248694]
[18]
Monteiro P, Feng G. SHANK proteins: Roles at the synapse and in autism spectrum disorder. Nat Rev Neurosci 2017; 18(3): 147-57.
[http://dx.doi.org/10.1038/nrn.2016.183] [PMID: 28179641]
[19]
Böckers TM, Segger-Junius M, Iglauer P, et al. Differential expression and dendritic transcript localization of Shank family members: identification of a dendritic targeting element in the 3′ untranslated region of Shank1 mRNA. Mol Cell Neurosci 2004; 26(1): 182-90.
[http://dx.doi.org/10.1016/j.mcn.2004.01.009] [PMID: 15121189]
[20]
Zitzer H, Hönck HH, Bächner D, Richter D, Kreienkamp HJ. Somatostatin receptor interacting protein defines a novel family of multidomain proteins present in human and rodent brain. J Biol Chem 1999; 274(46): 32997-3001.
[http://dx.doi.org/10.1074/jbc.274.46.32997] [PMID: 10551867]
[21]
Luo P, Fei F, Zhang L, Qu Y, Fei Z. The role of glutamate receptors in traumatic brain injury: Implications for postsynaptic density in pathophysiology. Brain Res Bull 2011; 85(6): 313-20.
[http://dx.doi.org/10.1016/j.brainresbull.2011.05.004] [PMID: 21605633]
[22]
Collins SM, Belagodu AP, Reed SL, Galvez R. SHANK1 is differentially expressed during development in CA1 hippocampal neurons and astrocytes. Dev Neurobiol 2018; 78(4): 363-73.
[http://dx.doi.org/10.1002/dneu.22564] [PMID: 29218848]
[23]
Caraci F, Battaglia G, Sortino MA, et al. Metabotropic glutamate receptors in neurodegeneration/neuroprotection: Still a hot topic? Neurochem Int 2012; 61(4): 559-65.
[http://dx.doi.org/10.1016/j.neuint.2012.01.017] [PMID: 22306345]
[24]
Spampinato SF, Copani A, Nicoletti F, Sortino MA, Caraci F. Metabotropic glutamate receptors in glial cells: A new potential target for neuroprotection? Front Mol Neurosci 2018; 11: 414.
[http://dx.doi.org/10.3389/fnmol.2018.00414] [PMID: 30483053]
[25]
Chen T, Fei F, Jiang X, et al. Down-regulation of Homer1b/c attenuates glutamate-mediated excitotoxicity through endoplasmic reticulum and mitochondria pathways in rat cortical neurons. Free Radic Biol Med 2012; 52(1): 208-17.
[http://dx.doi.org/10.1016/j.freeradbiomed.2011.10.451] [PMID: 22080088]
[26]
Hayashi MK, Tang C, Verpelli C, et al. The postsynaptic density proteins Homer and Shank form a polymeric network structure. Cell 2009; 137(1): 159-71.
[http://dx.doi.org/10.1016/j.cell.2009.01.050] [PMID: 19345194]
[27]
Hung AY, Futai K, Sala C, et al. Smaller dendritic spines, weaker synaptic transmission, but enhanced spatial learning in mice lacking Shank1. J Neurosci 2008; 28(7): 1697-708.
[http://dx.doi.org/10.1523/JNEUROSCI.3032-07.2008] [PMID: 18272690]
[28]
Hetz C, Axten JM, Patterson JB. Pharmacological targeting of the unfolded protein response for disease intervention. Nat Chem Biol 2019; 15(8): 764-75.
[http://dx.doi.org/10.1038/s41589-019-0326-2] [PMID: 31320759]
[29]
Park JS, Mehta P, Cooper AA, et al. Pathogenic effects of novel mutations in the P-type ATPase ATP13A2 (PARK9) causing Kufor-Rakeb syndrome, a form of early-onset parkinsonism. Hum Mutat 2011; 32(8): 956-64.
[http://dx.doi.org/10.1002/humu.21527] [PMID: 21542062]
[30]
Lee JH, Han J, Kim H, Park SM, Joe E, Jou I. Parkinson’s disease-associated LRRK2-G2019S mutant acts through regulation of SERCA activity to control ER stress in astrocytes. Acta Neuropathol Commun 2019; 7(1): 68.
[http://dx.doi.org/10.1186/s40478-019-0716-4] [PMID: 31046837]
[31]
Valdés P, Mercado G, Vidal RL, et al. Control of dopaminergic neuron survival by the unfolded protein response transcription factor XBP1. Proc Natl Acad Sci USA 2014; 111(18): 6804-9.
[http://dx.doi.org/10.1073/pnas.1321845111] [PMID: 24753614]
[32]
Sun HN, Kim SU, Huang SM, et al. Microglial peroxiredoxin V acts as an inducible anti-inflammatory antioxidant through cooperation with redox signaling cascades. J Neurochem 2010; 114(1): 39-55.
[http://dx.doi.org/10.1111/j.1471-4159.2010.06691.x] [PMID: 20345759]
[33]
Huh JY, Kim Y, Jeong J, et al. Peroxiredoxin 3 is a key molecule regulating adipocyte oxidative stress, mitochondrial biogenesis, and adipokine expression. Antioxid Redox Signal 2012; 16(3): 229-43.
[http://dx.doi.org/10.1089/ars.2010.3766] [PMID: 21902452]
[34]
Hu W, Dang XB, Wang G, Li S, Zhang YL. Peroxiredoxin-3 attenuates traumatic neuronal injury through preservation of mitochondrial function. Neurochem Int 2018; 114: 120-6.
[http://dx.doi.org/10.1016/j.neuint.2018.02.004] [PMID: 29427714]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy