期刊
CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS
卷 9, 期 4, 页码 439-454出版社
BENTHAM SCIENCE PUBL
DOI: 10.2174/187152710791556113
关键词
Alzheimer's disease; Parkinson's disease; amyotrophic lateral sclerosis; Huntington's disease; oxidative stress; mitochondria; autophagy; mitochondrial dynamics
资金
- Plan Nacional de I+D [SAF2006-06780, SAF2008-02199, SAF2008-04974, SAF2009-11417]
- Instituto de Salud Carlos III [PI070193, PI0900056, CIBEREHD]
- Research Center for Liver and Pancreatic Diseases, US National Institute on Alcohol Abuse and Alcoholism [P50-AA-11999]
Oxidative stress has been consistently linked to ageing-related neurodegenerative diseases leading to the generation of lipid peroxides, carbonyl proteins and oxidative DNA damage in tissue samples from affected brains. Studies from mouse models that express disease-specific mutant proteins associated to the major neurodegenerative processes have underscored a critical role of mitochondria in the pathogenesis of these diseases. There is strong evidence that mitochondrial dysfunction is an early event in neurodegeneration. Mitochondria are the main cellular source of reactive oxygen species and key regulators of cell death. Moreover, mitochondria are highly dynamic organelles that divide, fuse and move along axons and dendrites to supply cellular energetic demands; therefore, impairment of any of these processes would directly impact on neuronal viability. Most of the disease-specific pathogenic mutant proteins have been shown to target mitochondria, promoting oxidative stress and the mitochondrial apoptotic pathway. In addition, disease-specific mutant proteins may also impair mitochondrial dynamics and recycling of damaged mitochondria via autophagy. Collectively, these data suggest that ROS-mediated defective mitochondria may accumulate during and contribute to disease progression. Strategies aimed to improve mitochondrial function or ROS scavenging may thus be of potential clinical relevance.
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