Loss of PINK1 function affects development and results in neurodegeneration in zebrafish.
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, GSK3beta-related mechanisms can account for some of the effects of PINK1 knockdown, as morphant fish show elevated GSK3beta activity and their phenotype is partially abrogated by GSK3beta 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.
Anichtchik
Oleg
O
Summit, Waterbeach, Cambridge CB25 9TN, United Kingdom. oa220@cam.ac.uk
Diekmann
Heike
H
Fleming
Angeleen
A
Roach
Alan
A
Goldsmith
Paul
P
Rubinsztein
David C
DC
D000818:Animals; D001369:Axons / Q000201:enzymology / Q000473:pathology; D016923:Cell Death / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006801:Humans; D009410:Nerve Degeneration / Q000196:embryology / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D010641:Phenotype; D011494:Protein Kinases / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D000099202:PTEN-Induced Putative Kinase
D011494:Protein Kinases; D029961:Zebrafish Proteins; D000099202:PTEN-Induced Putative Kinase