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The Journal of Neuroscience, August 13, 2008, 28(33):8199-8207; doi:10.1523/JNEUROSCI.0979-08.2008
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Neurobiology of Disease
Loss of PINK1 Function Affects Development and Results in Neurodegeneration in Zebrafish
Oleg Anichtchik,1 Heike Diekmann,1 Angeleen Fleming,1 Alan Roach,1 Paul Goldsmith,1,2 andDavid C. Rubinsztein3 1Summit, Waterbeach, Cambridge CB25 9TN, United Kingdom, 2Department of Neurology, Addenbrooke's Hospital, Cambridge CB2 2QQ, United Kingdom, and 3Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 2XY, United Kingdom
Correspondence should be addressed to either of the following: Oleg Anichtchik at his present address, Cambridge Centre for Brain Repair/Department of Clinical Neuroscience, E. D. Adrian Building, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK, Email: oa220{at}cam.ac.uk; or David C. Rubinsztein, Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY UK, Email: dcr1000{at}hermes.cam.ac.uk
Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder in the Western world. PTEN (phosphatase/tensin homolog on chromosome 10)-induced putative kinase 1 (PINK1), a putative kinase that is mutated in autosomal recessive forms of PD, is also implicated in sporadic cases of the disease. Although the mutations appear to result in a loss of function, the roles of this protein and the pathways involved in PINK1 PD are poorly understood. Here, we generated a vertebrate model of PINK1 insufficiency using morpholino oligonucleotide knockdown in zebrafish (Danio rerio). PINK1 knockdown results in a severe developmental phenotype that is rescued by wild-type human PINK1 mRNA. Morphants display a moderate decrease in the numbers of central dopaminergic neurons and alterations of mitochondrial function, including increases in caspase-3 activity and reactive oxygen species (ROS) levels. When the morphants were exposed to several drugs with antioxidant properties, ROS levels were normalized and the associated phenotype improved. In addition, GSK3β-related mechanisms can account for some of the effects of PINK1 knockdown, as morphant fish show elevated GSK3β activity and their phenotype is partially abrogated by GSK3β inhibitors, such as LiCl and SB216763 [3-(2,4-dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)1H-pyrrole-2,5-dione]. This provides new insights into the biology of PINK1 and a possible therapeutic avenue for further investigation.
Key words: Parkinson's disease; zebrafish; neurodegeneration; mitochondria; ROS; PINK1
Received Nov. 16, 2007; revised July 1, 2008; accepted July 4, 2008.
Correspondence should be addressed to either of the following: Oleg Anichtchik at his present address, Cambridge Centre for Brain Repair/Department of Clinical Neuroscience, E. D. Adrian Building, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK, Email: oa220{at}cam.ac.uk; or David C. Rubinsztein, Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY UK, Email: dcr1000{at}hermes.cam.ac.uk
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[Abstract] [Full Text] [PDF]
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