Mitochondrial dysfunction in Parkinson's disease: molecular mechanisms and pathophysiological consequences

被引：449

作者：

Exner, Nicole ^{[2
]}

Lutz, Anne Kathrin ^{[1
,2
]}

Haass, Christian ^{[1
,2
]}

Winklhofer, Konstanze F. ^{[1
,2
]}

机构：

[1] German Ctr Neurodegenerat Dis DZNE Munich, D-80336 Munich, Germany

[2] Univ Munich, Adolf Butenandt Inst, Munich, Germany

来源：

EMBO JOURNAL | 2012年 / 31卷 / 14期

关键词：

mitochondria; parkin; Parkinson; PINK1; synuclein; COMPLEX-I DEFICIENCY; GENOME-WIDE ASSOCIATION; TUMOR-SUPPRESSOR GENE; RECESSIVE JUVENILE PARKINSONISM; SYNUCLEIN TRANSGENIC MICE; LACKING ALPHA-SYNUCLEIN; CYSTEINE-SULFINIC ACID; NEURONAL CELL-DEATH; LOSS-OF-FUNCTION; KINASE; LRRK2;

D O I：

10.1038/emboj.2012.170

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Neurons are critically dependent on mitochondrial integrity based on specific morphological, biochemical, and physiological features. They are characterized by high rates of metabolic activity and need to respond promptly to activity-dependent fluctuations in bioenergetic demand. The dimensions and polarity of neurons require efficient transport of mitochondria to hot spots of energy consumption, such as presynaptic and postsynaptic sites. Moreover, the postmitotic state of neurons in combination with their exposure to intrinsic and extrinsic neuronal stress factors call for a high fidelity of mitochondrial quality control systems. Consequently, it is not surprising that mitochondrial alterations can promote neuronal dysfunction and degeneration. In particular, mitochondrial dysfunction has long been implicated in the etiopathogenesis of Parkinson's disease (PD), based on the observation that mitochondrial toxins can cause parkinsonism in humans and animal models. Substantial progress towards understanding the role of mitochondria in the disease process has been made by the identification and characterization of genes causing familial variants of PD. Studies on the function and dysfunction of these genes revealed that various aspects of mitochondrial biology appear to be affected in PD, comprising mitochondrial biogenesis, bioenergetics, dynamics, transport, and quality control. The EMBO Journal (2012) 31, 3038-3062. doi: 10.1038/emboj.2012.170; Published online 26 June 2012

引用

页码：3038 / 3062

页数：25

共 384 条

[11] Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease [J].

Barrett, Jeffrey C. ;

Hansoul, Sarah ;

Nicolae, Dan L. ;

Cho, Judy H. ;

Duerr, Richard H. ;

Rioux, John D. ;

Brant, Steven R. ;

Silverberg, Mark S. ;

Taylor, Kent D. ;

Barmada, M. Michael ;

Bitton, Alain ;

Dassopoulos, Themistocles ;

Datta, Lisa Wu ;

Green, Todd ;

Griffiths, Anne M. ;

Kistner, Emily O. ;

Murtha, Michael T. ;

Regueiro, Miguel D. ;

Rotter, Jerome I. ;

Schumm, L. Philip ;

Steinhart, A. Hillary ;

Targan, Stephan R. ;

Xavier, Ramnik J. ;

Libioulle, Cecile ;

Sandor, Cynthia ;

Lathrop, Mark ;

Belaiche, Jacques ;

Dewit, Olivier ;

Gut, Ivo ;

Heath, Simon ;

Laukens, Debby ;

Mni, Myriam ;

Rutgeerts, Paul ;

Van Gossum, Andre ;

Zelenika, Diana ;

Franchimont, Denis ;

Hugot, Jean-Pierre ;

de Vos, Martine ;

Vermeire, Severine ;

Louis, Edouard ;

Cardon, Lon R. ;

Anderson, Carl A. ;

Drummond, Hazel ;

Nimmo, Elaine ;

Ahmad, Tariq ;

Prescott, Natalie J. ;

Onnie, Clive M. ;

Fisher, Sheila A. ;

Marchini, Jonathan ;

Ghori, Jilur .

NATURE GENETICS, 2008, 40 (08) :955-962

[12] α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation [J].

Bartels, Tim ;

Choi, Joanna G. ;

Selkoe, Dennis J. .

NATURE, 2011, 477 (7362) :107-U123

[13] Constructing and decoding unconventional ubiquitin chains [J].

Behrends, Christian ;

Harper, J. Wade .

NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2011, 18 (05) :520-528

[14] High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease [J].

Bender, A ;

Krishnan, KJ ;

Morris, CM ;

Taylor, GA ;

Reeve, AK ;

Perry, RH ;

Jaros, E ;

Hersheson, JS ;

Betts, J ;

Klopstock, T ;

Taylor, RW ;

Turnbull, DM .

NATURE GENETICS, 2006, 38 (05) :515-517

[15] Parkin selectively alters the intrinsic threshold for mitochondrial cytochrome c release [J].

Berger, Alison K. ;

Cortese, Giuseppe P. ;

Amodeo, Katherine D. ;

Weihofen, Andreas ;

Letai, Anthony ;

LaVoie, Matthew J. .

HUMAN MOLECULAR GENETICS, 2009, 18 (22) :4317-4328

[16] LRRK2 signaling pathways: the key to unlocking neurodegeneration? [J].

Berwick, Daniell C. ;

Harvey, Kirsten .

TRENDS IN CELL BIOLOGY, 2011, 21 (05) :257-265

[17] Mechanistic aspects of Parkinson's disease:: α-synuclein and the biomembrane [J].

Beyer, Klaus .

CELL BIOCHEMISTRY AND BIOPHYSICS, 2007, 47 (02) :285-299

[18] A Tale on Animal Models of Parkinson's Disease [J].

Bezard, Erwan ;

Przedborski, Serge .

MOVEMENT DISORDERS, 2011, 26 (06) :993-1002

[19] Localization of LRRK2 to membranous and vesicular structures in mammalian brain [J].

Biskup, Saskia ;

Moore, Darren J. ;

Celsi, Fulvio ;

Higashi, Shinji ;

West, Andrew B. ;

Andrabi, Shaida A. ;

Kurkinen, Kaisa ;

Yu, Seong-Woon ;

Savitt, Joseph M. ;

Waldvogel, Henry J. ;

Faull, Richard L. M. ;

Emson, Piers C. ;

Torp, Reldun ;

Ottersen, Ole P. ;

Dawson, Ted M. ;

Dawson, Valina L. .

ANNALS OF NEUROLOGY, 2006, 60 (05) :557-569

[20] Formation of a Stabilized Cysteine Sulfinic Acid Is Critical for the Mitochondrial Function of the Parkinsonism Protein DJ-1 [J].

Blackinton, Jeff ;

Lakshminarasimhan, Mahadevan ;

Thomas, Kelly J. ;

Ahmad, Rili ;

Greggio, Elisa ;

Raza, Ashraf S. ;

Cookson, Mark R. ;

Wilson, Mark A. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2009, 284 (10) :6476-6485

← 1 2 3 4 5 6 7 8 9 10 →