Brain region specific mitophagy capacity could contribute to selective neuronal vulnerability in Parkinson's disease

Proteome Science

Lei Mao²  Joachim Klose²  Claus Zabel²  Jie Shen¹  Andrea Koppelstaetter²  Grit Nebrich²  Tohru Kitada¹  Madeleine Diedrich² 

[1] Center for Neurologic Diseases, Brigham and Women's Hospital, Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA;Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, D-13353 Berlin, Germany

关键词: 2DE;    PINK1;    proteomics;    mitophagy;    Parkinson's disease;   

Others  :  820348
DOI  :  10.1186/1477-5956-9-59

 received in 2011-05-25, accepted in 2011-09-23,  发布年份 2011

【 摘 要 】

Parkinson's disease (PD) is histologically well defined by its characteristic degeneration of dopaminergic neurons in the substantia nigra pars compacta. Remarkably, divergent PD-related mutations can generate comparable brain region specific pathologies. This indicates that some intrinsic region-specificity respecting differential neuron vulnerability exists, which codetermines the disease progression. To gain insight into the pathomechanism of PD, we investigated protein expression and protein oxidation patterns of three different brain regions in a PD mouse model, the PINK1 knockout mice (PINK1-KO), in comparison to wild type control mice. The dysfunction of PINK1 presumably affects mitochondrial turnover by disturbing mitochondrial autophagic pathways. The three brain regions investigated are the midbrain, which is the location of substantia nigra; striatum, the major efferent region of substantia nigra; and cerebral cortex, which is more distal to PD pathology. In all three regions, mitochondrial proteins responsible for energy metabolism and membrane potential were significantly altered in the PINK1-KO mice, but with very different region specific accents in terms of up/down-regulations. This suggests that disturbed mitophagy presumably induced by PINK1 knockout has heterogeneous impacts on different brain regions. Specifically, the midbrain tissue seems to be most severely hit by defective mitochondrial turnover, whereas cortex and striatum could compensate for mitophagy nonfunction by feedback stimulation of other catabolic programs. In addition, cerebral cortex tissues showed the mildest level of protein oxidation in both PINK1-KO and wild type mice, indicating either a better oxidative protection or less reactive oxygen species (ROS) pressure in this brain region. Ultra-structural histological examination in normal mouse brain revealed higher incidences of mitophagy vacuoles in cerebral cortex than in striatum and substantia nigra. Taken together, the delicate balance between oxidative protection and mitophagy capacity in different brain regions could contribute to brain region-specific pathological patterns in PD.

【 授权许可】

   
2011 Diedrich et al; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Lees AJ, Hardy J, Revesz T: Parkinson's disease. Lancet 2009, 373:2055-66.
• [2]Dauer W, Przedborski S: Parkinson's disease: mechanisms and models. Neuron 2003, 39:889-909.
• [3]Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K: Stages in the development of Parkinson's disease-related pathology. Cell Tissue Res 2004, 318:121-34.
• [4]Mouradian MM: Recent advances in the genetics and pathogenesis of Parkinson disease. Neurology 2002, 58:179-85.
• [5]Bossy-Wetzel E, Schwarzenbacher R, Lipton SA: Molecular pathways to neurodegeneration. Nat Med 2004, 10(Suppl):S2-9.
• [6]Dawson TM, Dawson VL: Molecular pathways of neurodegeneration in Parkinson's disease. Science 2003, 302:819-22.
• [7]Diedrich M, Mao L, Bernreuther C, Zabel C, Nebrich G, Kleene R, Klose J: Proteome analysis of ventral midbrain in MPTP-treated normal and L1cam transgenic mice. Proteomics 2008, 8:1266-75.
• [8]Watanabe Y, Himeda T, Araki T: Mechanisms of MPTP toxicity and their implications for therapy of Parkinson's disease. Med Sci Monit 2005, 11:RA17-23.
• [9]Albanese A, Valente EM, Romito LM, Bellacchio E, Elia AE, Dallapiccola B: The PINK1 phenotype can be indistinguishable from idiopathic Parkinson disease. Neurology 2005, 64:1958-60.
• [10]Asanuma M, Miyazaki I, Ogawa N: Dopamine- or L-DOPA-induced neurotoxicity: the role of dopamine quinone formation and tyrosinase in a model of Parkinson's disease. Neurotox Res 2003, 5:165-76.
• [11]Pawelek JM, Lerner AB: 5, 6-Dihydroxyindole is a melanin precursor showing potent cytotoxicity. Nature 1978, 276:626-8.
• [12]Reeve AK, Krishnan KJ, Turnbull DM: Age related mitochondrial degenerative disorders in humans. Biotechnol J 2008, 3:750-6.
• [13]Van Laar VS, Berman SB: Mitochondrial dynamics in Parkinson's disease. Exp Neurol 2009, 218:247-56.
• [14]Kitada T, Pisani A, Porter DR, Yamaguchi H, Tscherter A, Martella G, Bonsi P, Zhang C, Pothos EN, Shen J: Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice. Proc Natl Acad Sci USA 2007, 104:11441-6.
• [15]van Nuenen BF, Weiss MM, Bloem BR, Reetz K, van Eimeren T, Lohmann K, Hagenah J, Pramstaller PP, Binkofski F, Klein C, Siebner HR: Heterozygous carriers of a Parkin or PINK1 mutation share a common functional endophenotype. Neurology 2009, 72:1041-7.
• [16]Hatano Y, Li Y, Sato K, Asakawa S, Yamamura Y, Tomiyama H, Yoshino H, Asahina M, Kobayashi S, Hassin-Baer S, Lu CS, Ng AR, Rosales RL, Shimizu N, Toda T, Mizuno Y, Hattori N: Novel PINK1 mutations in early-onset parkinsonism. Ann Neurol 2004, 56:424-7.
• [17]Ibanez P, Lesage S, Lohmann E, Thobois S, De Michele G, Borg M, Agid Y, Durr A, Brice A: Mutational analysis of the PINK1 gene in early-onset parkinsonism in Europe and North Africa. Brain 2006, 129:686-94.
• [18]Valente EM, Salvi S, Ialongo T, Marongiu R, Elia AE, Caputo V, Romito L, Albanese A, Dallapiccola B, Bentivoglio AR: PINK1 mutations are associated with sporadic early-onset parkinsonism. Ann Neurol 2004, 56:336-41.
• [19]Vives-Bauza C, Przedborski S: PINK1 points Parkin to mitochondria. Autophagy 2010, 6:5.
• [20]Narendra D, Tanaka A, Suen DF, Youle RJ: Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 2008, 183:795-803.
• [21]Gautier CA, Kitada T, Shen J: Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress. Proc Natl Acad Sci USA 2008, 105:11364-9.
• [22]Klose J, Kobalz U: Two-dimensional electrophoresis of proteins: an updated protocol and implications for a functional analysis of the genome. Electrophoresis 1995, 16:1034-59.
• [23]Kultima K, Scholz B, Alm H, Skold K, Svensson M, Crossman AR, Bezard E, Andren PE, Lonnstedt I: Normalization and expression changes in predefined sets of proteins using 2D gel electrophoresis: a proteomic study of L-DOPA induced dyskinesia in an animal model of Parkinson's disease using DIGE. BMC Bioinformatics 2006, 7:475. BioMed Central Full Text
• [24]Zabel C, Klose J: High-resolution large-gel 2DE: Methods. Mol Biol 2009, 519:311-38.
• [25]Gibson F, Anderson L, Babnigg G, Baker M, Berth M, Binz PA, Borthwick A, Cash P, Day BW, Friedman DB, Garland D, Gutstein HB, Hoogland C, Jones NA, Khan A, Klose J, Lamond AI, Lemkin PF, Lilley KS, Minden J, Morris NJ, Paton NW, Pisano MR, Prime JE, Rabilloud T, Stead DA, Taylor CF, Voshol H, Wipat A, Jones AR: Guidelines for reporting the use of gel electrophoresis in proteomics. Nat Biotechnol 2008, 26:863-4.
• [26]Zabel C, Sagi D, Kaindl AM, Steireif N, Klare Y, Mao L, Peters H, Wacker MA, Kleene R, Klose J: Comparative proteomics in neurodegenerative and non-neurodegenerative diseases suggest nodal point proteins in regulatory networking. J Proteome Res 2006, 5:1948-58.
• [27]Nebrich G, Herrmann M, Sagi D, Klose J, Giavalisco P: High MS-compatibility of silver nitrate-stained protein spots from 2-DE gels using ZipPlates and AnchorChips for successful protein identification. Electrophoresis 2007, 28:1607-14.
• [28]Pappin DJ, Hojrup P, Bleasby AJ: Rapid identification of proteins by peptide-mass fingerprinting. Curr Biol 1993, 3:327-32.
• [29]Klose J: Genotypes and phenotypes. Electrophoresis 1999, 20:643-52.
• [30]Bachmann S, Schlichting U, Geist B, Mutig K, Petsch T, Bacic D, Wagner CA, Kaissling B, Biber J, Murer H, Willnow TE: Kidney-specific inactivation of the megalin gene impairs trafficking of renal inorganic sodium phosphate cotransporter (NaPi-IIa). J Am Soc Nephrol 2004, 15:892-900.
• [31]Mao L, Zabel C, Wacker MA, Nebrich G, Sagi D, Schrade P, Bachmann S, Kowald A, Klose J: Estimation of the mtDNA mutation rate in aging mice by proteome analysis and mathematical modeling. Exp Gerontol 2006, 41:11-24.
• [32]Kaindl AM, Sifringer M, Koppelstaetter A, Genz K, Loeber R, Boerner C, Stuwe J, Klose J, Felderhoff-Mueser U: Erythropoietin protects the developing brain from hyperoxia-induced cell death and proteome changes. Ann Neurol 2008, 64:523-34.
• [33]Chen H, Chan DC: Mitochondrial dynamics--fusion, fission, movement, and mitophagy--in neurodegenerative diseases. Hum Mol Genet 2009, 18:R169-76.
• [34]Melendez A, Neufeld TP: The cell biology of autophagy in metazoans: a developing story. Development 2008, 135:2347-60.
• [35]Mijaljica D, Prescott M, Klionsky DJ, Devenish RJ: Autophagy and vacuole homeostasis: a case for self-degradation? Autophagy 2007, 3:417-21.
• [36]Stroikin Y, Dalen H, Brunk UT, Terman A: Testing the "garbage" accumulation theory of ageing: mitotic activity protects cells from death induced by inhibition of autophagy. Biogerontology 2005, 6:39-47.
• [37]Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, Albanese A, Nussbaum R, Gonzalez-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks WP, Latchman DS, Harvey RJ, Dallapiccola B, Auburger G, Wood NW: Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 2004, 304:1158-60.
• [38]Pearce RK, Owen A, Daniel S, Jenner P, Marsden CD: Alterations in the distribution of glutathione in the substantia nigra in Parkinson's disease. J Neural Transm 1997, 104:661-77.
• [39]Mizushima N, Levine B: Autophagy in mammalian development and differentiation. Nat Cell Biol 2010, 12:823-30.
• [40]Gegg ME, Schapira AH: PINK1-parkin-dependent mitophagy involves ubiquitination of mitofusins 1 and 2: Implications for Parkinson disease pathogenesis. Autophagy 2011, 7:2.
• [41]Ziviani E, Tao RN, Whitworth AJ: Drosophila parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin. Proc Natl Acad Sci USA 2010, 107:5018-23.
• [42]Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA, Shen J, Cookson MR, Youle RJ: PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol 2010, 8:e1000298.