Human Molecular Genetics Advance Access originally published online on July 13, 2009
Human Molecular Genetics 2009 18(19):3659-3672; doi:10.1093/hmg/ddp314
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Pantothenate kinase-associated neurodegeneration: insights from a Drosophila model
State Key Laboratory of Biomembrane and Membrane Biotechnology, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing 100084, China
* To whom correspondence should be addressed. Tel: +86 1062795322; Fax: +86 1062772253; Email: zhoubing{at}mail.tsinghua.edu.cn
Received April 22, 2009; Revised June 9, 2009; Accepted July 6, 2009
Pantothenate-Kinase-Associated-Neurodegeneration (PKAN) is a devastating disease, resulting from mutations in pantothenate kinase 2 (PANK2), one of the four human pantothenate kinase genes (PANK1-4). Interestingly, PanK2 appears to be the only mitochondria-targeted human PanK. It is unknown whether the mitochondria-targeted PanK is associated with any unique function, nor whether PKAN is due solely to the loss of pantothenate kinase activity. Drosophila PANK [fumble (fbl)] encodes several isoforms of pantothenate kinase products, one of which localizes to mitochondria and the others cytosol. fbl flies exhibit many characteristic features reminiscent of PKAN patients. Various forms of Drosophila fbl and human PANK2 were introduced into fbl flies to study their in vivo functions. Only mitochondria-targeted Fbl or human PanK2 was able to rescue fbl mutation, with the rescuing ability sensitive to the expression level of the transgene. Transgenic lines with low expression of normal Fbl or PanK2 displayed similar phenotypes as PANK2 mutant transgenic flies. These PanK2 mutants all showed reduced and phenotype severity-correlated in vitro pantothenate kinase activities. Amazingly, cytosolic PanK3 and PanK4 could mostly, but not fully, rescue fbl defects except the male sterility. Therefore, fbl appears to be the orthologue of human PANK2, and PanK2 is functionally more potent than PanK3 and PanK4 in vivo. We suggest that mitochondria-located pantothenate kinase is required to achieve the maximal enzymatic activity to fulfill the most challenging task such as maintaining male fertility and optimal neuronal functions, and PKAN features are mainly due to the reduction of the total cellular pantothenate kinase activity in the most susceptible regions.