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The role of impaired De novo Coenzyne A biosynthesis in pantothenate kinase-associated neurodegeneration : insight from a Drosophila model

(2010) Rana, Anil

Pantothenate kinase-associated neurodegeneration (PKAN, OMIM 234200) is an autosomal recessive, progressive neurodegenerative disorder. PKAN is caused by mutations in pantothenate kinase 2 (PANK2), the gene that encodes an enzyme (PANK2) which is a rate limiting enzyme in de novo Coenzyme A (CoA) biosynthesis. Interestingly, in humans there are four highly homologous PANK genes (PANK1-4) however; only mutations in PANK2 but not in the other PANK genes, are associated with PKAN. Mutations in PANK1, 3, 4 have also never been reported to be associated with any other diseases or pathologies, suggesting that, these genes are essential for life, or their functions may be redundant. Since PANK is the first and the rate limiting enzyme in de novo CoA biosynthesis, the suggestion was postulated that impairment of de novo CoA biosynthesis might underlie the pathogenesis of PKAN [1]. Interestingly, among the four PANKs, only PANK2 is targeted to the mitochondria and these organelles have the highest concentration of total cellular pool of CoA. Therefore, it was also proposed that a mitochondrial deficiency of CoA biosynthesis results in the PKAN disorder. In order to investigate these hypotheses and to understand how a deficiency in PANK2 might give rise to the neuropathology of PKAN, a mouse PANK2 knock-out model was generated [2].Unfortunately, the mouse model was unable to recapitulate the neurodegenerative symptoms of PKAN. Therefore, currently, the PKAN pathology remains complex and far from understood and due to the lack of a proper PKAN model, the speculated role of impaired de novo CoA remained uninvestigated.
In addition, the rarity of PKAN patients (1:3,000,000) complicates investigating PKAN pathology, because patient material is extremely sparse. Drosophila is a well established
model organism to understand mechanisms in health and disease and also based on the above, it would be helpful for PKAN-related research to have a Drosophila PKAN model. Here, we explored the possibilities of Drosophila as a model for PKAN and we investigated the implicated role of impaired de novo CoA biosynthesis in the pathogenesis of this devastating disease. Specifically we were interested in determining; 1) whether the PANK deficiency in Drosophila indeed leads to a CoA deficiency. 2) Whether CoA deficiency in an organism (Drosophila) can lead to a neurodegenerative disorder. If successful, our aim was to use the power of the Drosophila model to screen various compounds, which can ameliorate the PKAN disease characteristics.

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