Mitochondrial and Cell Death Mechanisms in Neurodegenerative Diseases
Abstract
:Introduction
Types of Cell Death
Cell Necrosis and the Mitochondrial Permeability Transition Pore
Protein | Function |
---|---|
Bcl-2* | Anti-apoptotic, blocks Bax/Bak channel formation |
Bcl-XL | Anti-apoptotic, blocks Bax/Bak channel formation |
Bax* | Pro-apoptotic, forms pores for cytochrome c release |
Bak* | Pro-apoptotic, forms pores for cytochrome c release |
Bad | Pro-apoptotic, decoy for Bcl-2/Bcl-XL promoting Bax/Bak pore formation |
Bid | Pro-apoptotic, decoy for Bcl-2/Bcl-XL promoting Bax/Bak pore formation |
Noxa | Pro-apoptotic, decoy for Bcl-2/Bcl-XL promoting Bax/Bak pore formation |
Puma | Pro-apoptotic, decoy for Bcl-2/Bcl-XL promoting Bax/Bak pore formation |
p53* | Antagonizes activity of Bcl-2/Bcl-XL, promotes Bax/Bak oligomerization |
Cytochrome c | Activator of apoptosome |
Smac/DIABLO | IAP inhibitor |
AIF | Antioxidant flavoprotein/released from mitochondria to promote nuclear DNA fragmentation |
Endonuclease G | Released from mitochondria to promote nuclear DNA fragmentation |
HtrA2/Omi | IAP inhibitor |
VDAC | mPTP component in outer mitochondrial membrane |
ANT+ | mPTP component in inner mitochondrial membrane |
Cyclophilin D+ | mPTP component in mitochondrial matrix |
TSPO (peripheral benzodiazepine receptor) | Modulator of mPTP |
Hexokinase | Modulator of VDAC |
Apoptosis
Autophagy
Cellular and Molecular Regulation of Apoptosis
Bcl-2 Family | Caspase Family | IAP Family | Tumor Suppressor | |
Anti-apoptotic proteins | Pro-apoptotic proteins | |||
Bcl-2 | Bax | Apoptosis “initiators”: caspase-2, 8, 9, 10 | NAIP | p53 |
Bcl-xL | Bak1 | Apollon | p63 | |
Mcl-1 | Bcl-xS | Survivin | p73 | |
Boo/Diva | Bad | Apoptosis “executioners”: caspase-2, 3, 6, 7 | IAP1 | |
Bid | IAP2 | |||
Bik | XIAP | |||
Bim | Cytokine processors: caspase-1, 4, 5, 11, 12, 14 | |||
Noxa | ||||
Puma |
Bcl-2 family of Cell Survival and Cell Death Proteins
Caspase Family of Cell Demolition Proteases
Inhibitor of Apoptosis Protein (IAP) Family
Apoptosis Inducing Factor (AIF)
p53/p63/p73 Family of Tumor Suppressors
Cell Surface Death Receptors
Excitotoxic Neuronal Cell Death
The Cell Death Continuum
The Cell Death Matrix
Cell Death in Human Neurodegenerative Diseases
Alzheimer’s disease (AD)
Most Tg Mouse Models of AD are not Useful to Study Neuronal Cell Death
Cell Culture Models of Cortical and Hippocampal Neuron Cell Death and Interactions between APP, Aβ, Tau, and Caspases
Parkinson’s Disease (PD)
Locus | Inheritance | Gene | Protein Name/ Function |
---|---|---|---|
PARK1/4q21 | autosomal dominant | α-syn | α-Syn/presynaptic maintenance? |
PARK2/6q25.2-27 | autosomal recessive | parkin | Parkin/ubiquitin E3 ligase |
PARK3/2p13 | autosomal dominant | ? | ? |
PARK4/4p15 | autosomal dominant | α-syn | α-Syn/presynaptic maintenance? |
PARK5/4p14 | autosomal dominant | UCHL1 | UCHL1/polyubiquitin hydrolase |
PARK6/1p36 | autosomal recessive | PINK1 | PTEN-induced putative kinase-1/mitochondrial protein kinase |
PARK7/1p36.33-36-12 | autosomal recessive | DJ-1 | DJ-1/mitochondrial antioxidant, chaperone |
PARK8/12q12 | autosomal dominant | LRRK2 | Dardarin/multifunctional kinase/GTPase |
PARK9/1p36 | autosomal recessive | ATP13A2 | Lysosomal type 5 P-ATPase |
PARK10/1p32 | ? | ? | |
PARK11/2q36-37 | autosomal dominant | GIGYF2? | Grb10-interacting GYP protein 2, modulates tyrosine kinase receptor signaling, including IGF-1 |
PARK12/Xq21-q25 | X-linked | ? | ? |
PARK13/2p12 | autosomal recessive susceptibility factor | Omi/HtrA2 | Omi/HtrA2, mitochondrial serine peptidase, inhibitor of IAPs |
PARK14/22q13.1 | autosomal recessive | PLA2G6 | Phospholipase A2 group VI |
PARK15/22q12-q13 | autosomal recessive | FBXO7 | F-box protein 7 |
Mutant Genes that Cause Some Forms of PD
α-Syn
UCH-L1 and Parkin
PINK1
DJ-1
LRRK2
Neuronal Cell Death in Human PD
PD α-Syn Tg Mice Develop Neuronal Mitochondrial Degeneration and Cell Death
ALS
Locus | Inheritance | Gene | Protein Name/ Function |
---|---|---|---|
ALS1/21q22 | autosomal dominant (adult onset) | SOD1 | Cu/Zn superoxide dismutase/ dismutation of superoxide |
ALS2/2q33.2 | autosomal recessive (juvenile onset primary lateral sclerosis) | Alsin | Alsin/guanine exchange factor for RAB5A and Rac1 |
ALS4/9q34 | autosomal dominant (adult onset) | SETX | Senataxin/helicase, RNA processing |
ALS6/16q12 | autosomal recessive (adult onset) | FUS | Fused in sarcoma, component of heterogeneous nuclear ribonuclear protein complex; RNA/DNA binding protein |
ALS8/20q13.33 | autosomal dominant | VAPB | VAMP-associated protein B/part of SNARE complex |
2q13 | autosomal dominant (adult onset, atypical ALS) | DCTN1 | Dynactin p150glued/axonal transport, link between dynein and microtubule network |
ALS10/1p36.22 | autosomal dominant | TARDBP | TAR DNA binding protein, DNA and RNA binding protein, regulates RNA splicing |
ALS11/6q21 | autosomal recessive | FIG4 | FIG4 homolog, SAC1 lipid phosphatase domain containing protein; regulates phosphotidylinositol turnover |
14q11.1-q11.2 | susceptibility factor | ANG | Angiogenin; angiogenesis; stimulates production of rRNA |
22q12.2 | susceptibility factor | NEFH | Neurofilament, heavy polypeptide; neurofilament subunit |
12q12-q13 | susceptibility factor | PRPH | Peripherin; intermediate filament formation |
5q13 | susceptibility factor | SMN | Survival motor neuron; RNA processing |
7q36.6 | susceptibility factor? | DPP6 | Dipeptidyl-peptidase 6; S9B serine protease, binds voltage-gated potassium channels |
Mitochondrial Dysfunction in Human ALS
Human ALS and Mitochondrial-Orchestrated PCD Involving p53
Mitochondrial Pathobiology in Cell and Mouse Models of ALS
The mPTP Contributes to the Disease Mechanisms of ALS in Mice
Summary and Outlook
Abbreviations
Aβ | amyloid beta protein |
AD | Alzheimer’s disease |
AIF | apoptosis-inducing factor |
ALS | amyotrophic lateral sclerosis |
ANT | adenine nucleotide translocator |
Apaf | apoptotic protease activating factor |
APP | amyloid precursor protein |
CNS | central nervous system |
Cu/ZnSOD | copper/zinc superoxide dismutase (also SOD1) |
CyPD | cyclophilin D |
DISC | death-inducing signaling complex |
EM | electron microscopy |
ER | endoplasmic reticulum |
GPe | globus pallidus external |
GPi | globus pallidus internal |
HtrA2 | high temperature requirement protein A2 |
IAP | inhibitor of apoptosis protein |
IMM | inner mitochondrial membrane |
KA | kainic acid |
LB | Lewy body |
LGN | lateral geniculate nucleus |
LRRK2 | leucine-rich repeat kinase 2 |
mnSOD | manganese SOD (also SOD2) |
mPT | mitochondrial permeability transition |
mPTP | mitochondrial permeability transition pore |
mSOD1 | mutant SOD1 |
mtDNA | mitochondrial DNA |
NAIP | neuronal apoptosis inhibitory protein |
NFT | neurofibrillary tangle |
NMDA | N-methy-D-aspartate |
NO | nitric oxide |
NOS | nitric oxide synthase |
O2•- | superoxide radical |
OMM | outer mitochondrial membrane |
ONOO- | peroxynitrite |
PCD | programmed cell death |
PD | Parkinson’s disease |
PINK1 | phosphatase and tensin homolog-induced putative kinase-1 |
ROS | reactive oxygen species |
SNc | substantia nigra compacta |
Syn | α-synuclein |
Tg | transgenic |
TIMM | translocase of inner mitochondrial membrane |
TOMM | translocase of outer mitochondrial membrane |
TSPO | translocator protein 18 kDa (peripheral benzodiazepine receptor) |
TNF | tumor necrosis factor |
TUNEL | terminal transferase-mediated biotin-dUTP nick-end labeling |
UCH-L1 | ubiquitin carboxy-terminal hydrolyase-L1 |
VDAC | voltage-dependent anion channel |
Acknowledgments
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Martin, L.J. Mitochondrial and Cell Death Mechanisms in Neurodegenerative Diseases. Pharmaceuticals 2010, 3, 839-915. https://doi.org/10.3390/ph3040839
Martin LJ. Mitochondrial and Cell Death Mechanisms in Neurodegenerative Diseases. Pharmaceuticals. 2010; 3(4):839-915. https://doi.org/10.3390/ph3040839
Chicago/Turabian StyleMartin, Lee J. 2010. "Mitochondrial and Cell Death Mechanisms in Neurodegenerative Diseases" Pharmaceuticals 3, no. 4: 839-915. https://doi.org/10.3390/ph3040839