PINK1 Deficiency Enhances Inflammatory Cytokine Release from Acutely Prepared Brain Slices

Overview

Journal Exp Neurobiol

Specialty Neurology

Date 2013 Apr 16

PMID 23585721

Citations 38

Authors

Jun Kim

Ji-Won Byun

Insup Choi

Beomsue Kim

Hey-Kyeong Jeong

Ilo Jou

Eunhye Joe

Affiliations

Soon will be listed here.

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative motor disease caused by degeneration of dopaminergic neurons in the substantia nigra. Because brain inflammation has been considered a risk factor for PD, we analyzed whether PTEN induced putative kinase 1 (PINK1), an autosomal recessive familial PD gene, regulates brain inflammation during injury states. Using acutely prepared cortical slices to mimic injury, we analyzed expression of the pro-inflammatory cytokines tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 at the mRNA and protein levels. Both mRNA and protein expression of these cytokines was higher at 6-24 h after slicing in PINK1 knockout (KO) slices compared to that in wild-type (WT) slices. In serial experiments to understand the signaling pathways that increase inflammatory responses in KO slices, we found that IκB degradation was enhanced but Akt phosphorylation decreased in KO slices compared to those in WT slices. In further experiments, an inhibitor of PI3K (LY294002) upstream of Akt increased expression of pro-inflammatory cytokines. Taken together, these results suggest that PINK1 deficiency enhance brain inflammation through reduced Akt activation and enhanced IκB degradation in response to brain injury.

Citing Articles

What Can Inflammation Tell Us about Therapeutic Strategies for Parkinson's Disease?.

Xue J, Tao K, Wang W, Wang X Int J Mol Sci. 2024; 25(3).

PMID: 38338925 PMC: 10855787. DOI: 10.3390/ijms25031641.

The Involvement of Neuroinflammation in the Onset and Progression of Parkinson's Disease.

Jurcau A, Andronie-Cioara F, Nistor-Cseppento D, Pascalau N, Rus M, Vasca E Int J Mol Sci. 2023; 24(19).

PMID: 37834030 PMC: 10573049. DOI: 10.3390/ijms241914582.

Circulating exosomes from brain death and cardiac death donors have distinct molecular and immunologic properties: A pilot study.

Ravichandran R, Itabashi Y, Zhou F, Lin Y, Mohanakumar T, Chapman W Clin Transplant. 2023; 37(10):e15067.

PMID: 37428019 PMC: 11019898. DOI: 10.1111/ctr.15067.

Outlook of PINK1/Parkin signaling in molecular etiology of Parkinson's disease, with insights into knockout models.

Wang Z, Chan S, Zhao H, Miu K, Chan W Zool Res. 2023; 44(3):559-576.

PMID: 37161651 PMC: 10236303. DOI: 10.24272/j.issn.2095-8137.2022.406.

Microglia Mediated Neuroinflammation in Parkinson's Disease.

Isik S, Yeman Kiyak B, Akbayir R, Seyhali R, Arpaci T Cells. 2023; 12(7).

PMID: 37048085 PMC: 10093562. DOI: 10.3390/cells12071012.

References

Cui H, Matsumoto K, Murakami Y, Hori H, Zhao Q, Obi R . Berberine exerts neuroprotective actions against in vitro ischemia-induced neuronal cell damage in organotypic hippocampal slice cultures: involvement of B-cell lymphoma 2 phosphorylation suppression. Biol Pharm Bull. 2009; 32(1):79-85. DOI: 10.1248/bpb.32.79. View

Wood-Kaczmar A, Gandhi S, Yao Z, Abramov A, Abramov A, Miljan E . PINK1 is necessary for long term survival and mitochondrial function in human dopaminergic neurons. PLoS One. 2008; 3(6):e2455. PMC: 2413012. DOI: 10.1371/journal.pone.0002455. View

Medina E, Morris I, Berton M . Phosphatidylinositol 3-kinase activation attenuates the TLR2-mediated macrophage proinflammatory cytokine response to Francisella tularensis live vaccine strain. J Immunol. 2010; 185(12):7562-72. DOI: 10.4049/jimmunol.0903790. View

Deng H, Jankovic J, Guo Y, Xie W, Le W . Small interfering RNA targeting the PINK1 induces apoptosis in dopaminergic cells SH-SY5Y. Biochem Biophys Res Commun. 2005; 337(4):1133-8. DOI: 10.1016/j.bbrc.2005.09.178. View

Skibo G, Nikonenko I, Savchenko V, McKanna J . Microglia in organotypic hippocampal slice culture and effects of hypoxia: ultrastructure and lipocortin-1 immunoreactivity. Neuroscience. 2000; 96(2):427-38. DOI: 10.1016/s0306-4522(99)00562-x. View

Valente E, Abou-Sleiman P, Caputo V, Muqit M, Harvey K, Gispert S . Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science. 2004; 304(5674):1158-60. DOI: 10.1126/science.1096284. View

Beal M . Mitochondria, oxidative damage, and inflammation in Parkinson's disease. Ann N Y Acad Sci. 2003; 991:120-31. DOI: 10.1111/j.1749-6632.2003.tb07470.x. View

Hald A, Lotharius J . Oxidative stress and inflammation in Parkinson's disease: is there a causal link?. Exp Neurol. 2005; 193(2):279-90. DOI: 10.1016/j.expneurol.2005.01.013. View

Choi I, Kim J, Jeong H, Kim B, Jou I, Park S . PINK1 deficiency attenuates astrocyte proliferation through mitochondrial dysfunction, reduced AKT and increased p38 MAPK activation, and downregulation of EGFR. Glia. 2013; 61(5):800-12. PMC: 3657120. DOI: 10.1002/glia.22475. View

10.

Huuskonen J, Suuronen T, Miettinen R, van Groen T, Salminen A . A refined in vitro model to study inflammatory responses in organotypic membrane culture of postnatal rat hippocampal slices. J Neuroinflammation. 2005; 2:25. PMC: 1298326. DOI: 10.1186/1742-2094-2-25. View

11.

Jeong H, Ji K, Kim B, Kim J, Jou I, Joe E . Inflammatory responses are not sufficient to cause delayed neuronal death in ATP-induced acute brain injury. PLoS One. 2010; 5(10):e13756. PMC: 2966428. DOI: 10.1371/journal.pone.0013756. View

12.

Min K, Jeong H, Kim B, Hwang D, Shin H, Nguyen A . Spatial and temporal correlation in progressive degeneration of neurons and astrocytes in contusion-induced spinal cord injury. J Neuroinflammation. 2012; 9:100. PMC: 3418552. DOI: 10.1186/1742-2094-9-100. View

13.

Zhang X, Smith D, Meriin A, Engemann S, Russel D, Roark M . A potent small molecule inhibits polyglutamine aggregation in Huntington's disease neurons and suppresses neurodegeneration in vivo. Proc Natl Acad Sci U S A. 2005; 102(3):892-7. PMC: 545525. DOI: 10.1073/pnas.0408936102. View

14.

Wei W, Nguyen L, Kessels H, Hagiwara H, Sisodia S, Malinow R . Amyloid beta from axons and dendrites reduces local spine number and plasticity. Nat Neurosci. 2009; 13(2):190-6. PMC: 3310198. DOI: 10.1038/nn.2476. View

15.

Mogi M, Harada M, Riederer P, Narabayashi H, Fujita K, Nagatsu T . Tumor necrosis factor-alpha (TNF-alpha) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients. Neurosci Lett. 1994; 165(1-2):208-10. DOI: 10.1016/0304-3940(94)90746-3. View

16.

Whitton P . Inflammation as a causative factor in the aetiology of Parkinson's disease. Br J Pharmacol. 2007; 150(8):963-76. PMC: 2013918. DOI: 10.1038/sj.bjp.0707167. View

17.

Wilms H, Zecca L, Rosenstiel P, Sievers J, Deuschl G, Lucius R . Inflammation in Parkinson's diseases and other neurodegenerative diseases: cause and therapeutic implications. Curr Pharm Des. 2007; 13(18):1925-8. DOI: 10.2174/138161207780858429. View

18.

Gispert S, Ricciardi F, Kurz A, Azizov M, Hoepken H, Becker D . Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration. PLoS One. 2009; 4(6):e5777. PMC: 2686165. DOI: 10.1371/journal.pone.0005777. View

19.

Akundi R, Huang Z, Eason J, Pandya J, Zhi L, Cass W . Increased mitochondrial calcium sensitivity and abnormal expression of innate immunity genes precede dopaminergic defects in Pink1-deficient mice. PLoS One. 2011; 6(1):e16038. PMC: 3020954. DOI: 10.1371/journal.pone.0016038. View

20.

Kretz-Remy C, Mehlen P, Mirault M, Arrigo A . Inhibition of I kappa B-alpha phosphorylation and degradation and subsequent NF-kappa B activation by glutathione peroxidase overexpression. J Cell Biol. 1996; 133(5):1083-93. PMC: 2120847. DOI: 10.1083/jcb.133.5.1083. View