Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 32, Pages 11364-11369Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0802076105
Keywords
neurodegeneration; PARK6; genetic Parkinson's disease; knockout; parkinsonism
Categories
Funding
- National Institute of Neurological Disorders and Stroke [R01 NS41779]
- American Parkinson's Disease Association
- Ecole Polytechnique (France)
Ask authors/readers for more resources
Parkinson's disease (PD) is a common neurodegenerative disorder thought to be associated with mitochondrial dysfunction. Loss of function mutations in the putative mitochondrial protein PINK1 (PTEN-induced kinase 1) have been linked to familial forms of PD, but the relation of PINK1 to mammalian mitochondrial function remains unclear. Here, we report that germline deletion of the PINK1 gene in mice significantly impairs mitochondrial functions. Quantitative electron microscopic studies of the striatum in PINK1(-/-) mice at 3-4 and 24 months revealed no gross changes in the ultrastructure or the total number of mitochondria, although the number of larger mitochondria is selectively increased. Functional assays showed impaired mitochondrial respiration in the striatum but not in the cerebral cortex at 3-4 months of age, suggesting specificity of this defect for dopaminergic circuitry. Aconitase activity associated with the Krebs cycle is also reduced in the striatum of PINK1(-/-) mice. Interestingly, mitochondrial respiration activities in the cerebral cortex are decreased in PINK1(-/-) mice at 2 years compared with control mice, indicating that aging can exacerbate mitochondrial dysfunction in these mice. Furthermore, mitochondrial respiration defects can be induced in the cerebral cortex of PINK1(-/-) mice by cellular stress, such as exposure to H2O2 or mild heat shock. Together, our findings demonstrate that mammalian PINK1 is important for mitochondrial function and provides critical protection against both intrinsic and environmental stress, suggesting a pathogenic mechanism by which loss of PINK1 may lead to nigrostriatal degeneration in PD.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available