Top

Published in:

01-04-2017 | Neurology and Preclinical Neurological Studies - Original Article

Age-dependent alpha-synuclein accumulation is correlated with elevation of mitochondrial TRPC3 in the brains of monkeys and mice

Authors: Min Chen, Jia Liu, Yongquan Lu, Chunli Duan, Lingling Lu, Ge Gao, Piu Chan, Shun Yu, Hui Yang

Published in: Journal of Neural Transmission | Issue 4/2017

Abstract

Aberrant α-synuclein (α-syn) accumulation has been shown to impair mitochondrial function by reducing mitochondrial membrane potential (MMP). However, the underlying mechanisms remain elusive. Transient receptor potential canonical (TRPC) channels are a diverse group of non-selective Ca²⁺ channels, among which TRPC3 is the only one that is localized in mitochondria and plays a role in maintaining the normal MMP. This raises a possibility that altered TRPC3 expression may play a role in the mitochondrial dysfunction induced by α-syn accumulation. To demonstrate this possibility, we first examined the expressions of mitochondrial TRPC3 in the brains of aging monkeys and α-syn transgenic and wild-type mice. We showed that α-syn levels increased in mitochondria in an age-dependent manner that was positively correlated to an elevation of mitochondrial TRPC3. This correlation was more prominent in the striatum than in the cerebellum, possibly due to the greater age-dependent α-syn accumulation in the striatum than in the cerebellum. We then used primary neurons overexpressing α-syn to investigate the effect of the α-syn-induced elevation of mitochondrial TRPC3 on the MMP and apoptotic cell death. We found that neurons with overexpressed α-syn had increased mitochondrial TRPC3 and decreased MMP, which were accompanied by increased number of apoptotic neurons. Suppressing TRPC3 expression partially reversed the reduction of MMP and alleviated the apoptotic cell death, indicating that the mitochondrial TRPC3 may play a role in the mitochondrial dysfunction in neurons with α-syn accumulation that may occur in not only the aged brain but also the brain with PD.

Bender A, Krishnan KJ, Morris CM, Taylor GA, Reeve AK, Perry RH, Jaros E, Hersheson JS, Betts J, Klopstock T, Taylor RW, Turnbull DM (2006) High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet 38(5):515–517. doi:10.1038/ng1769 CrossRefPubMed

Braak H, Rub U, Gai WP, Del Tredici K (2003) Idiopathic Parkinson’s disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm (Vienna) 110(5):517–536. doi:10.1007/s00702-002-0808-2 CrossRef

Branch SY, Chen C, Sharma R, Lechleiter JD, Li S, Beckstead MJ (2016) Dopaminergic neurons exhibit an age-dependent decline in electrophysiological parameters in the MitoPark Mouse Model of Parkinson’s disease. J Neurosci 36(14):4026–4037. doi:10.1523/JNEUROSCI.1395-15.2016 CrossRefPubMedPubMedCentral

Brown SV, Hosking P, Li J, Williams N (2006) ATP synthase is responsible for maintaining mitochondrial membrane potential in bloodstream form Trypanosoma brucei. Eukaryot Cell 5(1):45–53. doi:10.1128/EC.5.1.45-53.2006 CrossRefPubMedPubMedCentral

Brundin P, Li JY, Holton JL, Lindvall O, Revesz T (2008) Research in motion: the enigma of Parkinson’s disease pathology spread. Nat Rev Neurosci 9(10):741–745. doi:10.1038/nrn2477 CrossRefPubMed

Chen M, Yang W, Li X, Li X, Wang P, Yue F, Yang H, Chan P, Yu S (2016) Age- and brain region-dependent alpha-synuclein oligomerization is attributed to alterations in intrinsic enzymes regulating alpha-synuclein phosphorylation in aging monkey brains. Oncotarget 7(8):8466–8480. doi:10.18632/oncotarget.6445 PubMed

Chinta SJ, Mallajosyula JK, Rane A, Andersen JK (2010) Mitochondrial alpha-synuclein accumulation impairs complex I function in dopaminergic neurons and results in increased mitophagy in vivo. Neurosci Lett 486(3):235–239. doi:10.1016/j.neulet.2010.09.061 CrossRefPubMedPubMedCentral

Clapham DE (2003) TRP channels as cellular sensors. Nature 426(6966):517–524. doi:10.1038/nature02196 CrossRefPubMed

Colla E, Coune P, Liu Y, Pletnikova O, Troncoso JC, Iwatsubo T, Schneider BL, Lee MK (2012) Endoplasmic reticulum stress is important for the manifestations of alpha-synucleinopathy in vivo. J Neurosci 32(10):3306–3320. doi:10.1523/JNEUROSCI.5367-11.2012 CrossRefPubMedPubMedCentral

Del Tredici K, Braak H (2016) Review: sporadic Parkinson’s disease: development and distribution of alpha-synuclein pathology. Neuropathol Appl Neurobiol 42(1):33–50. doi:10.1111/nan.12298 CrossRefPubMed

Devi L, Raghavendran V, Prabhu BM, Avadhani NG, Anandatheerthavarada HK (2008) Mitochondrial import and accumulation of alpha-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain. J Biol Chem 283(14):9089–9100. doi:10.1074/jbc.M710012200 CrossRefPubMedPubMedCentral

Du TT, Wang L, Duan CL, Lu LL, Zhang JL, Gao G, Qiu XB, Wang XM, Yang H (2015) GBA deficiency promotes SNCA/alpha-synuclein accumulation through autophagic inhibition by inactivated PPP2A. Autophagy 11(10):1803–1820. doi:10.1080/15548627.2015.1086055 CrossRefPubMedPubMedCentral

Eder P, Probst D, Rosker C, Poteser M, Wolinski H, Kohlwein SD, Romanin C, Groschner K (2007) Phospholipase C-dependent control of cardiac calcium homeostasis involves a TRPC3-NCX1 signaling complex. Cardiovasc Res 73(1):111–119. doi:10.1016/j.cardiores.2006.10.016 CrossRefPubMed

Exner N, Lutz AK, Haass C, Winklhofer KF (2012) Mitochondrial dysfunction in Parkinson’s disease: molecular mechanisms and pathophysiological consequences. EMBO J 31(14):3038–3062. doi:10.1038/emboj.2012.170 CrossRefPubMedPubMedCentral

Feng S, Li H, Tai Y, Huang J, Su Y, Abramowitz J, Zhu MX, Birnbaumer L, Wang Y (2013) Canonical transient receptor potential 3 channels regulate mitochondrial calcium uptake. Proc Natl Acad Sci USA 110(27):11011–11016. doi:10.1073/pnas.1309531110 CrossRefPubMedPubMedCentral

Gonzalez-Horta A (2015) The interaction of alpha-synuclein with membranes and its implication in Parkinson’s disease: a literature review. Nat Prod Commun 10(10):1775–1778PubMed

Guo Y, Rosati B, Scarlata S (2012) Alpha–Synuclein increases the cellular level of phospholipase Cbeta1. Cell Signal 24(5):1109–1114. doi:10.1016/j.cellsig.2012.01.007 CrossRefPubMedPubMedCentral

Hartmann J, Konnerth A (2015) TRPC3-dependent synaptic transmission in central mammalian neurons. J Mol Med (Berl) 93(9):983–989. doi:10.1007/s00109-015-1298-7 CrossRef

Jellinger KA (2003) Alpha-synuclein pathology in Parkinson’s and Alzheimer’s disease brain: incidence and topographic distribution—a pilot study. Acta Neuropathol 106(3):191–201. doi:10.1007/s00401-003-0725-y CrossRefPubMed

Jellinger KA (2009) Formation and development of Lewy pathology: a critical update. J Neurol 256(Suppl 3):270–279. doi:10.1007/s00415-009-5243-y CrossRefPubMed

Jiang P, Gan M, Yen SH, Moussaud S, McLean PJ, Dickson DW (2016) Proaggregant nuclear factor(s) trigger rapid formation of alpha-synuclein aggregates in apoptotic neurons. Acta Neuropathol 132(1):77–91. doi:10.1007/s00401-016-1542-4 CrossRefPubMedPubMedCentral

Kim SR, Ries V, Cheng HC, Kareva T, Oo TF, Yu WH, Duff K, Kholodilov N, Burke RE (2011a) Age and alpha-synuclein expression interact to reveal a dependence of dopaminergic axons on endogenous Akt/PKB signaling. Neurobiol Dis 44(2):215–222. doi:10.1016/j.nbd.2011.07.003 CrossRefPubMedPubMedCentral

Kim SS, Moon KR, Choi HJ (2011b) Interference of alpha-synuclein with cAMP/PKA-dependent CREB signaling for tyrosine hydroxylase gene expression in SK-N-BE(2)C cells. Arch Pharm Res 34(5):837–845. doi:10.1007/s12272-011-0518-0 CrossRefPubMed

Lessard CB, Lussier MP, Cayouette S, Bourque G, Boulay G (2005) The overexpression of presenilin2 and Alzheimer’s-disease-linked presenilin2 variants influences TRPC6-enhanced Ca2+ entry into HEK293 cells. Cell Signal 17(4):437–445. doi:10.1016/j.cellsig.2004.09.005 CrossRefPubMed

Lichtenegger M, Groschner K (2014) TRPC3: a multifunctional signaling molecule. Handb Exp Pharmacol 222:67–84. doi:10.1007/978-3-642-54215-2_4 CrossRefPubMed

Liu G, Zhang C, Yin J, Li X, Cheng F, Li Y, Yang H, Ueda K, Chan P, Yu S (2009) alpha-Synuclein is differentially expressed in mitochondria from different rat brain regions and dose-dependently down-regulates complex I activity. Neurosci Lett 454(3):187–192. doi:10.1016/j.neulet.2009.02.056 CrossRefPubMed

Liu G, Chen M, Mi N, Yang W, Li X, Wang P, Yin N, Li Y, Yue F, Chan P, Yu S (2015) Increased oligomerization and phosphorylation of alpha-synuclein are associated with decreased activity of glucocerebrosidase and protein phosphatase 2A in aging monkey brains. Neurobiol Aging 36(9):2649–2659. doi:10.1016/j.neurobiolaging.2015.06.004 CrossRefPubMed

Lu L, Zhang C, Cai Q, Lu Q, Duan C, Zhu Y, Yang H (2013) Voltage-dependent anion channel involved in the alpha-synuclein-induced dopaminergic neuron toxicity in rats. Acta Biochim Biophys Sin (Shanghai) 45(3):170–178. doi:10.1093/abbs/gms114 CrossRef

Ludtmann MH, Angelova PR, Ninkina NN, Gandhi S, Buchman VL, Abramov AY (2016) Monomeric alpha-synuclein exerts a physiological role on brain ATP synthase. J Neurosci 36(41):10510–10521. doi:10.1523/JNEUROSCI.1659-16.2016 CrossRefPubMedPubMedCentral

Lui JC, Kong SK (2007) Heat shock protein 70 inhibits the nuclear import of apoptosis-inducing factor to avoid DNA fragmentation in TF-1 cells during erythropoiesis. FEBS Lett 581(1):109–117. doi:10.1016/j.febslet.2006.11.082 CrossRefPubMed

Musgrove RE, King AE, Dickson TC (2013) alpha-Synuclein protects neurons from apoptosis downstream of free-radical production through modulation of the MAPK signalling pathway. Neurotox Res 23(4):358–369. doi:10.1007/s12640-012-9352-5 CrossRefPubMed

Nakamura K, Nemani VM, Azarbal F, Skibinski G, Levy JM, Egami K, Munishkina L, Zhang J, Gardner B, Wakabayashi J, Sesaki H, Cheng Y, Finkbeiner S, Nussbaum RL, Masliah E, Edwards RH (2011) Direct membrane association drives mitochondrial fission by the Parkinson disease-associated protein alpha-synuclein. J Biol Chem 286(23):20710–20726. doi:10.1074/jbc.M110.213538 CrossRefPubMedPubMedCentral

Ottolini D, Cali T, Szabo I, Brini M (2016) Alpha-synuclein at the intracellular and the extracellular side: functional and dysfunctional implications. Biol Chem. doi:10.1515/hsz-2016-0201

Perfeito R, Lazaro DF, Outeiro TF, Rego AC (2014) Linking alpha-synuclein phosphorylation to reactive oxygen species formation and mitochondrial dysfunction in SH-SY5Y cells. Mol Cell Neurosci 62:51–59. doi:10.1016/j.mcn.2014.08.002 CrossRefPubMed

Rockenstein E, Mallory M, Hashimoto M, Song D, Shults CW, Lang I, Masliah E (2002) Differential neuropathological alterations in transgenic mice expressing alpha-synuclein from the platelet-derived growth factor and Thy-1 promoters. J Neurosci Res 68(5):568–578. doi:10.1002/jnr.10231 CrossRefPubMed

Rodriguez M, Rodriguez-Sabate C, Morales I, Sanchez A, Sabate M (2015) Parkinson’s disease as a result of aging. Aging Cell 14(3):293–308. doi:10.1111/acel.12312 CrossRefPubMedPubMedCentral

Rostovtseva TK, Gurnev PA, Protchenko O, Hoogerheide DP, Yap TL, Philpott CC, Lee JC, Bezrukov SM (2015) Alpha-synuclein shows high affinity interaction with voltage-dependent anion channel, suggesting mechanisms of mitochondrial regulation and toxicity in Parkinson disease. J Biol Chem 290(30):18467–18477. doi:10.1074/jbc.M115.641746 CrossRefPubMedPubMedCentral

Schapira AH, Jenner P (2011) Etiology and pathogenesis of Parkinson’s disease. Mov Disord 26(6):1049–1055. doi:10.1002/mds.23732 CrossRefPubMed

Schapira AH, Cooper JM, Dexter D, Jenner P, Clark JB, Marsden CD (1989) Mitochondrial complex I deficiency in Parkinson’s disease. Lancet 1(8649):1269CrossRefPubMed

Selvaraj S, Sun Y, Singh BB (2010) TRPC channels and their implication in neurological diseases. CNS Neurol Disord: Drug Targets 9(1):94–104CrossRef

Shen J, Du T, Wang X, Duan C, Gao G, Zhang J, Lu L, Yang H (2014) alpha-Synuclein amino terminus regulates mitochondrial membrane permeability. Brain Res 1591:14–26. doi:10.1016/j.brainres.2014.09.046 CrossRefPubMed

Silvestri L, Caputo V, Bellacchio E, Atorino L, Dallapiccola B, Valente EM, Casari G (2005) Mitochondrial import and enzymatic activity of PINK1 mutants associated to recessive parkinsonism. Hum Mol Genet 14(22):3477–3492. doi:10.1093/hmg/ddi377 CrossRefPubMed

Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M (1998) alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with lewy bodies. Proc Natl Acad Sci USA 95(11):6469–6473CrossRefPubMedPubMedCentral

Sumi-Akamaru H, Beck G, Shinzawa K, Kato S, Riku Y, Yoshida M, Fujimura H, Tsujimoto Y, Sakoda S, Mochizuki H (2016) High expression of alpha-synuclein in damaged mitochondria with PLA2G6 dysfunction. Acta Neuropathol Commun 4:27. doi:10.1186/s40478-016-0298-3 CrossRefPubMedPubMedCentral

Tzoulis C, Schwarzlmuller T, Biermann M, Haugarvoll K, Bindoff LA (2016) Mitochondrial DNA homeostasis is essential for nigrostriatal integrity. Mitochondrion 28:33–37. doi:10.1016/j.mito.2016.03.003 CrossRefPubMed

Xu W, Tan L, Yu JT (2015) Link between the SNCA gene and parkinsonism. Neurobiol Aging 36(3):1505–1518. doi:10.1016/j.neurobiolaging.2014.10.042 CrossRefPubMed

Yang W, Wang X, Duan C, Lu L, Yang H (2013) Alpha-synuclein overexpression increases phospho-protein phosphatase 2A levels via formation of calmodulin/Src complex. Neurochem Int 63(3):180–194. doi:10.1016/j.neuint.2013.06.010 CrossRefPubMed

Yu S, Chan P (2014) Role of alpha-synuclein in neurodegeneration: implications for the pathogenesis of Parkinson’s disease. Essays Biochem 56:125–135. doi:10.1042/bse0560125 CrossRefPubMed

Yu S, Li X, Liu G, Han J, Zhang C, Li Y, Xu S, Liu C, Gao Y, Yang H, Ueda K, Chan P (2007) Extensive nuclear localization of alpha-synuclein in normal rat brain neurons revealed by a novel monoclonal antibody. Neuroscience 145(2):539–555. doi:10.1016/j.neuroscience.2006.12.028 CrossRefPubMed

Zhang H, Liu J, Wang X, Duan C, Wang X, Yang H (2016) V63 and N65 of overexpressed alpha-synuclein are involved in mitochondrial dysfunction. Brain Res 1642:308–318. doi:10.1016/j.brainres.2016.04.002 CrossRefPubMed

Zheng B, Liao Z, Locascio JJ, Lesniak KA, Roderick SS, Watt ML, Eklund AC, Zhang-James Y, Kim PD, Hauser MA, Grunblatt E, Moran LB, Mandel SA, Riederer P, Miller RM, Federoff HJ, Wullner U, Papapetropoulos S, Youdim MB, Cantuti-Castelvetri I, Young AB, Vance JM, Davis RL, Hedreen JC, Adler CH, Beach TG, Graeber MB, Middleton FA, Rochet JC, Scherzer CR, Global PDGEC (2010) PGC-1alpha, a potential therapeutic target for early intervention in Parkinson’s disease. Sci Transl Med 2 (52):52ra73. doi:10.1126/scitranslmed.3001059

Zhu X, Jiang M, Peyton M, Boulay G, Hurst R, Stefani E, Birnbaumer L (1996) trp, a novel mammalian gene family essential for agonist-activated capacitative Ca2+ entry. Cell 85(5):661–671CrossRefPubMed

Zhu Y, Duan C, Lu L, Gao H, Zhao C, Yu S, Ueda K, Chan P, Yang H (2011) alpha-Synuclein overexpression impairs mitochondrial function by associating with adenylate translocator. Int J Biochem Cell Biol 43(5):732–741. doi:10.1016/j.biocel.2011.01.014 CrossRefPubMed

Title: Age-dependent alpha-synuclein accumulation is correlated with elevation of mitochondrial TRPC3 in the brains of monkeys and mice
Authors: Min Chen
Jia Liu
Yongquan Lu
Chunli Duan
Lingling Lu
Ge Gao
Piu Chan
Shun Yu
Hui Yang
Publication date: 01-04-2017
Publisher: Springer Vienna
Published in: Journal of Neural Transmission / Issue 4/2017
Print ISSN: 0300-9564
Electronic ISSN: 1435-1463
DOI: https://doi.org/10.1007/s00702-016-1654-y

At a glance: The STEP trials

Springer Medicine

Age-dependent alpha-synuclein accumulation is correlated with elevation of mitochondrial TRPC3 in the brains of monkeys and mice

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2017

The insertion/deletion polymorphism in the angiotensin-converting enzyme gene and nicotine dependence in schizophrenia patients

Deep brain stimulation for dystonia: a novel perspective on the value of genetic testing

Comparative analysis of speech impairment and upper limb motor dysfunction in Parkinson’s disease

The dopamine-related polymorphisms BDNF, COMT, DRD2, DRD3, and DRD4 are not linked with changes in CSF dopamine levels and frequency of HIV infection

Differential behavioral outcomes following neonatal versus fetal human retinal pigment epithelial cell striatal implants in parkinsonian rats

Mutation screening of PLA2G6 in Japanese patients with early onset dystonia-parkinsonism