Abstract
Alterations in the basal ganglia circuitry are critical events in the pathophysiology of Parkinson’s disease (PD). We earlier compared MPTP-susceptible C57BL/6J and MPTP-resistant CD-1 mice to understand the differential prevalence of PD in different ethnic populations like Caucasians and Asian-Indians. The MPTP-resistant CD-1 mice had 33% more nigral neurons and lost only 15–17% of them following MPTP administration. In addition to other cytomorphological features, their basal ganglia neurons had higher calcium-buffering protein levels. During disease pathogenesis as well as in MPTP-induced parkinsonian models, the loss of nigral neurons is associated with reduction in mitochondrial complex-1. Under these conditions, mitochondria respond by undergoing fusion or fission. 17β-hydroxysteroid type 10, i.e., hydroxysteroid dehydrogenase10 (HSD10) and dynamin-related peptide1 (Drp1) are proteins involved in mitochondrial hyperfusion and fission, respectively. Each plays an important role in mitochondrial structure and homeostasis. Their role in determining susceptibility to the neurotoxin MPTP in basal ganglia is however unclear. We studied their expression using immunohistochemistry and Western blotting in the dorsolateral striatum, ventral tegmental area, and substantia nigra pars compacta (SNpc) of C57BL/6J and CD-1 mice. In the SNpc, which exhibits more neuron loss following MPTP, C57BL/6J had higher baseline Drp1 levels; suggesting persistence of fission under normal conditions. Whereas, HSD10 levels increased in CD-1 following MPTP administration. This suggests mitochondrial hyperfusion, as an attempt towards neuroprotection. Thus, the baseline differences in HSD10 and DRP1 levels as well as their contrasting MPTP-responses may be critical determinants of the magnitude of neuronal loss/survival. Similar differences may determine the variable susceptibility to PD in humans.
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References
Alexander GE (1994) Basal ganglia-thalamocortical circuits: their role in control of movements. J Clin Neurophysiol 11(4):420–431 Available at: http://www.ncbi.nlm.nih.gov/pubmed/7962489. Accessed 16 May 2018
Alladi PA, Mahadevan A, Yasha TC, Raju TR, Shankar SK, Muthane U (2009) Absence of age-related changes in nigral dopaminergic neurons of Asian Indians: relevance to lower incidence of Parkinson’s disease. Neuroscience 159(1):236–245. https://doi.org/10.1016/j.neuroscience.2008.11.051
Alladi PA, Mahadevan A, Vijayalakshmi K, Muthane U, Shankar SK, Raju TR (2010a) Ageing enhances alpha-synuclein, ubiquitin and endoplasmic reticular stress protein expression in the nigral neurons of Asian Indians. Neurochem Int 57(5):530–539
Alladi PA, Mahadevan A, Shankar SK, Raju TR, Muthane U (2010b) Expression of GDNF receptors GFRalpha1 and RET is preserved in substantia nigra pars compacta of aging Asian Indians. J Chem Neuroanat 40(1):43–52
Arduíno, D. M., Esteves, A. R. and Cardoso, S. M. (2011) ‘Mitochondrial fusion/fission, transport and autophagy in Parkinson’s disease: when mitochondria get nasty.’, Parkinson’s Dis Hindawi, 2011, p. 767230. doi: https://doi.org/10.4061/2011/767230
Ayala A, Venero JL, Cano J, Machado A (2007) Mitochondrial toxins and neurodegenerative diseases. Front Biosci 12:986–1007 Available at: http://www.ncbi.nlm.nih.gov/pubmed/17127354. Accessed 6 Sept 2018
Barsoum MJ, Yuan H, Gerencser AA, Liot G, Kushnareva Y, Gräber S, Kovacs I, Lee WD, Waggoner J, Cui J, White AD, Bossy B, Martinou JC, Youle RJ, Lipton SA, Ellisman MH, Perkins GA, Bossy-Wetzel E (2006) Nitric oxide-induced mitochondrial fission is regulated by dynamin-related GTPases in neurons. EMBO J Eur Mol Biol Organ 25(16):3900–3911. https://doi.org/10.1038/sj.emboj.7601253
Bereiter-Hahn J (1990) Behavior of mitochondria in the living cell. Int Rev Cytol 122(C):1–63. https://doi.org/10.1016/S0074-7696(08)61205-X
Bertolin G, Jacoupy M, Traver S, Ferrando-Miguel R, Saint Georges T, Grenier K, Ardila-Osorio H, Muriel MP, Takahashi H, Lees AJ, Gautier C, Guedin D, Coge F, Fon EA, Brice A, Corti O (2015) Parkin maintains mitochondrial levels of the protective Parkinson’s disease-related enzyme 17-β hydroxysteroid dehydrogenase type 10. Cell Death Differ Nature Publishing Group 22(10):1563–1576. https://doi.org/10.1038/cdd.2014.224
Bhaduri B, Abhilash PL, Alladi PA (2018) Baseline striatal and nigral interneuronal protein levels in two distinct mice strains differ in accordance with their MPTP susceptibility. J Chem Neuroanat 22(91):46–54. https://doi.org/10.1016/j.jchemneu.2018.04.005
Browne SE, Flint Beal M (2002) Toxin-induced mitochondrial dysfunction. pp 243–279. https://doi.org/10.1016/S0074-7742(02)53010-5
Burns RS, Chiueh CC, Markey SP, Ebert MH, Jacobowitz DM, Kopin IJ. (1983) A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. In: Proceedings of the National Academy of Sciences of the United States of America, vol 80(14). National Academy of Sciences, pp 4546–50. Available at: http://www.ncbi.nlm.nih.gov/pubmed/6192438. Accessed: 31 Aug 2018
Chiba K, Trevor A, Castagnoli N (1984) Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase. Biochem Biophys Res Commun 120(2):574–578 Available at: http://www.ncbi.nlm.nih.gov/pubmed/6428396. Accessed 4 Sept 2018
Corral-Debrinski M, Horton T, Lott MT, Shoffner JM, Beal MF, Wallace DC (1992) Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nat Genet 2(4):324–329. https://doi.org/10.1038/ng1292-324
Das SK, Misra AK, Ray BK, Hazra A, Ghosal MK, Chaudhuri A, Roy T, Banerjee TK, Raut DK (2010) Epidemiology of Parkinson disease in the city of Kolkata, India: a community-based study. Neurology. Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology 75(15):1362–1369. https://doi.org/10.1212/WNL.0b013e3181f735a7
Filichia E, Hoffer B, Qi X, Luo Y (2016) Inhibition of Drp1 mitochondrial translocation provides neural protection in dopaminergic system in a Parkinson’s disease model induced by MPTP. Sci Rep. Nature Publishing Group 6(1):32656. https://doi.org/10.1038/srep32656
Gao J, Wang L, Liu J, Xie F, Su B, Wang X (2017) Abnormalities of mitochondrial dynamics in neurodegenerative diseases. Antioxidants 6(2):25. https://doi.org/10.3390/antiox6020025
Gibrat C, Saint-Pierre M, Bousquet M, Lévesque D, Rouillard C, Cicchetti F (2009) Differences between subacute and chronic MPTP mice models: investigation of dopaminergic neuronal degeneration and α-synuclein inclusions. J Neurochem 109(5):1469–1482. https://doi.org/10.1111/j.1471-4159.2009.06072.x
Giovanni A, Sieber BA, Heikkila RE, Sonsalla PK (1991) Correlation between the neostriatal content of the 1-methyl-4-phenylpyridinium species and dopaminergic neurotoxicity following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration to several strains of mice. J Pharmacol Exp Ther 257(2):691–697 Available at: http://www.ncbi.nlm.nih.gov/pubmed/2033514. Accessed 31 Aug 2018
Grohm J, Kim SW, Mamrak U, Tobaben S, Cassidy-Stone A, Nunnari J, Plesnila N, Culmsee C (2012) Inhibition of Drp1 provides neuroprotection in vitro and in vivo. Cell Death Differ. Nat Publ Group 19(9):1446–1458. https://doi.org/10.1038/cdd.2012.18
Hamre K, Tharp R, Poon K, Xiong X, Smeyne RJ (1999) Differential strain susceptibility following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration acts in an autosomal dominant fashion: quantitative analysis in seven strains of Mus musculus. Brain Res 828(1–2):91–103 Available at: http://www.ncbi.nlm.nih.gov/pubmed/10320728. Accessed 8 Sept 2018
Hirsch E, Graybiel AM, Agid YA (1988) Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson’s disease. Nature. Nature Publishing Group 334(6180):345–348. https://doi.org/10.1038/334345a0
Hu C, Huang Y, Li L (2017) Drp1-dependent mitochondrial fission plays critical roles in physiological and pathological progresses in mammals. Int J Mol Sci. Multidisciplinary Digital Publishing Institute (MDPI). 18(1). https://doi.org/10.3390/ijms18010144
Ikebe S, Tanaka M, Ohno K, Sato W, Hattori K, Kondo T, Mizuno Y, Ozawa T (1990) Increase of deleted mitochondrial DNA in the striatum in Parkinson’s disease and senescence. Biochem Biophys Res Commun Academic Press 170(3):1044–1048. https://doi.org/10.1016/0006-291X(90)90497-B
Irwin I, William Langston J (1985) II. Selective accumulation of MPP+ in the substantia nigra: a key to neurotoxicity? Life Sci. Pergamon 36(3):207–212. https://doi.org/10.1016/0024-3205(85)90060-8
Jackson-Lewis V, Przedborski S (2007) Protocol for the MPTP mouse model of Parkinson’s disease. Nat Protoc 2(1):141–151. https://doi.org/10.1038/nprot.2006.342
Jiang N, Bo H, Song C, Guo J, Zhao F, Feng H, Ding H, Ji L, Zhang Y (2014) Increased vulnerability with aging to MPTP: the mechanisms underlying mitochondrial dynamics. Neurol Res 36(8):722–732. https://doi.org/10.1179/1743132813Y.0000000296
Jyothi HJ, Vidyadhara DJ, Mahadevan A, Philip M, Parmar SK, Manohari SG, Shankar SK, Raju TR, Alladi PA (2015) Aging causes morphological alterations in astrocytes and microglia in human substantia nigra pars compacta. Neurobiol Aging 36(12):3321–3333
Kohutnicka M1, Lewandowska E, Kurkowska-Jastrzebska I, Członkowski A, Członkowska A (1998) Microglial and astrocytic involvement in a murine model of Parkinson’s disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Immunopharmacology 39(3):167–180 Available at: http://www.ncbi.nlm.nih.gov/pubmed/9754903. Accessed 8 May 2018
Lewis TL Jr, Kwon SK, Lee A, Shaw R, Polleux F (2018) MFF-dependent mitochondrial fission regulates presynaptic release and axon branching by limiting axonal mitochondria size. Nat Commun 9(1):5008. https://doi.org/10.1038/s41467-018-07416-2
Meredith GE, Rademacher DJ (2011) MPTP mouse models of Parkinson’s disease: an update. J Parkinson’s Dis. NIH Public Access 1(1):19–33. https://doi.org/10.3233/JPD-2011-11023
Morigaki R, Goto S (2016) Putaminal mosaic visualized by tyrosine hydroxylase immunohistochemistry in the human neostriatum. Front Neuroanat Front 10:34. https://doi.org/10.3389/fnana.2016.00034
Muthane U, Ramsay KA, Jiang H, Jackson-Lewis V, Donaldson D, Fernando S, Ferreira M, Przedborski S (1994) Differences in nigral neuron number and sensitivity to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in C57/bl and CD-1 mice. Exp Neurol 126(2):195–204. https://doi.org/10.1006/exnr.1994.1058
Naskar A, Mahadevan A, Philip M, Alladi PA (2019) Aging mildly affects dendritic arborisation and synaptic protein expression in human substantia nigra pars compacta. J Chem Neuroanat 97:57–65. https://doi.org/10.1016/j.jchemneu.2019.02.001
Nass R, Przedborski S (2008) Parkinson’s disease: molecular and therapeutic insights from model systems. Elsevier Academic Press. Available at: https://books.google.co.in/books?id=oDE713MMJCEC&pg=PA152&lpg=PA152&dq=Neuromelanin+GRANULES+mice+brain+pd&source=bl&ots=MauzUj1ers&sig=3BEGvO4a745w7qmKvGVqchuwY74&hl=en&sa=X&ved=0ahUKEwiM8Ouu35zYAhWBq48KHSR5ChQQ6AEIcDAP#v=onepage&q&f=false. Accessed 22 Dec 2017
Naydenov AV, Vassoler F, Luksik AS, Kaczmarska J, Konradi C (2010) Mitochondrial abnormalities in the putamen in Parkinson’s disease dyskinesia. Acta Neuropathol. NIH Public Access 120(5):623–631. https://doi.org/10.1007/s00401-010-0740-8
Rappold PM, Cui M, Grima JC, Fan RZ, de Mesy-Bentley KL, Chen L, Zhuang X, Bowers WJ, Tieu K (2014) Drp1 inhibition attenuates neurotoxicity and dopamine release deficits in vivo. Nat Commun. Nat Publ Group 5:1–13. https://doi.org/10.1038/ncomms6244
Rauschenberger K, Schöler K, Sass JO, Sauer S, Djuric Z, Rumig C, Wolf NI, Okun JG, Kölker S, Schwarz H, Fischer C, Grziwa B, Runz H, Nümann A, Shafqat N, Kavanagh KL, Hämmerling G, Wanders RJ, Shield JP, Wendel U, Stern D, Nawroth P, Hoffmann GF, Bartram CR, Arnold B, Bierhaus A, Oppermann U, Steinbeisser H, Zschocke J (2010) A non-enzymatic function of 17beta-hydroxysteroid dehydrogenase type 10 is required for mitochondrial integrity and cell survival. EMBO Mol Med. Wiley-Blackwell 2(2):51–62. https://doi.org/10.1002/emmm.200900055
Sato S, Hattori N (2011) Genetic mutations and mitochondrial toxins shed new light on the pathogenesis of Parkinson’s disease. Parkinson’s Dis. Hindawi 2011:979231. https://doi.org/10.4061/2011/979231
Schoenberg BS, Osuntokun BO, Adeuja AO, Bademosi O, Nottidge V, Anderson DW, Haerer AF (1988) Comparison of the prevalence of Parkinson's disease in black populations in the rural United States and in rural Nigeria: door-to-door community studies. Neurology 38(4):645–646
Song DD, Haber SN (2000) Striatal responses to partial dopaminergic lesion: evidence for compensatory sprouting. J Neurosci 20(13):5102–5114 Available at: http://www.ncbi.nlm.nih.gov/pubmed/10864967. Accessed 14 Sept 2018
Stephen L, Archer MD (2013) Mitochondrial dynamics—mitochondrial fission and fusion in human diseases. N Engl J Med 369(23):2236–2251 Available at: http://deptmed.queensu.ca/assets/Announcement_Images/NEJM_Mitochondrial_Dynamics.pdf. Accessed 7 May 2018
Strickland D, Bertoni JM (2004) Parkinson’s prevalence estimated by a state registry. Mov Disord Wiley-Blackwell 19(3):318–323. https://doi.org/10.1002/mds.10619
Tieu K, Perier C, Vila M, Caspersen C, Zhang HP, Teismann P, Jackson-Lewis V, Stern DM, Yan SD, Przedborski S (2004) L-3-hydroxyacyl-CoA dehydrogenase II protects in a model of Parkinson’s disease. Ann Neurol 56(1):51–60. https://doi.org/10.1002/ana.20133
Tysnes O-B, Storstein A (2017) Epidemiology of Parkinson’s disease. J Neural Transm. Springer Vienna 124(8):901–905. https://doi.org/10.1007/s00702-017-1686-y
Van Den Eeden SK, Tanner CM, Bernstein AL, Fross RD, Leimpeter A, Bloch DA, Nelson LM (2003) Incidence of Parkinson’s disease: variation by age, gender, and race/ethnicity. Am J Epidemiol 157(11):1015–1022
Varastet M, Riche D, Maziere M, Hantraye P (1994) Chronic MPTP treatment reproduces in baboons the differential vulnerability of mesencephalic dopaminergic neurons observed in Parkinson’s disease. Neuroscience Pergamon 63(1):47–56. https://doi.org/10.1016/0306-4522(94)90006-X
Vidyadhara DJ, Yarreiphang H, Abhilash PL, Raju TR, Alladi PA (2016) Differential expression of calbindin in nigral dopaminergic neurons in two mice strains with differential susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. J Chem Neuroanat. 2016 Oct;76(Pt B):82–89. https://doi.org/10.1016/j.jchemneu.2016.01.001
Vidyadhara DJ, Yarreiphang H, Raju TR, Alladi PA (2017) Admixing of MPTP-resistant and susceptible mice strains augments nigrostriatal neuronal correlates to resist MPTP-induced neurodegeneration. Mol Neurobiol 54(8):6148–6162. https://doi.org/10.1007/s12035-016-0158-y
Vidyadhara DJ, Sasidharan A, Kutty BM, Raju TR, Alladi PA (2019) Admixing MPTP-resistant and MPTP-vulnerable mice enhances striatal field potentials and calbindin-D28K expression to avert motor behaviour deficits. Behav Brain Res 360:216–227. https://doi.org/10.1016/j.bbr.2018.12.015
Vyas I, Heikkila RE, Nicklas WJ (1986) Studies on the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: inhibition of NAD-linked substrate oxidation by its metabolite, 1-methyl-4-phenylpyridinium. J Neurochem 46(5):1501–1507 Available at: http://www.ncbi.nlm.nih.gov/pubmed/3485701. Accessed 5 Sept 2018
Wai T, Langer T (2016) Mitochondrial dynamics and metabolic regulation. Trends Endocrinol Metab 27(2):105–117. https://doi.org/10.1016/j.tem.2015.12.001
Wang X, Su B, Liu W, He X, Gao Y, Castellani RJ, Perry G, Smith MA, Zhu X (2011) DLP1-dependent mitochondrial fragmentation mediates 1-methyl-4-phenylpyridinium toxicity in neurons: implications for Parkinson’s disease. Aging Cell. NIH Public Access 10(5):807–823. https://doi.org/10.1111/j.1474-9726.2011.00721.x.
Willems PH, Rossignol R, Dieteren CE, Murphy MP, Koopman WJ (2015) Redox homeostasis and mitochondrial dynamics. Cell Metabolism. Elsevier Inc 22(2):207–218. https://doi.org/10.1016/j.cmet.2015.06.006
Wirdefeldt K, Adami HO, Cole P, Trichopoulos D, Mandel J (2011) Epidemiology and etiology of Parkinson’s disease: a review of the evidence. Eur J Epidemiol 26(1):1–58
Zschocke J, Ruiter JP, Brand J, Lindner M, Hoffmann GF, Wanders RJ, Mayatepek E (2000) Progressive infantile neurodegeneration caused by 2-methyl-3-Hydroxybutyryl-CoA dehydrogenase deficiency: a novel inborn error of branched-chain fatty acid and isoleucine metabolism. Pediatr Res 48(6):852–855. https://doi.org/10.1203/00006450-200012000-00025
Acknowledgements
The authors are grateful to Dr. G.H. Mohan, Head Veterinarian at the National Centre for Biological Sciences, Bengaluru, for providing breeding colonies of the CD-1 mice strain. We thank Dr. Vidyadhara D.J. and Dr. Yarreiphang H. for their help in initiating the experiments.
Funding
This work was supported by the Science and Engineering Research Board, Department of Science and Technology, Government of India, to PAA (No. SR/SO/HS-0121/2012). SA is a NIMHANS M.Phil. fellow.
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Seshadri, A., Alladi, P.A. Divergent Expression Patterns of Drp1 and HSD10 in the Nigro-Striatum of Two Mice Strains Based on their MPTP Susceptibility. Neurotox Res 36, 27–38 (2019). https://doi.org/10.1007/s12640-019-00036-8
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DOI: https://doi.org/10.1007/s12640-019-00036-8