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Abstract
Pantothenate Kinase-Associated Neurodegeneration (PKAN) is a neurodegenerative disorder with a poorly understood molecular mechanism. It is caused by mutations in Pantothenate Kinase, the first enzyme in the Coenzyme A (CoA) biosynthetic pathway. Here, we developed a Drosophila model of PKAN (tim-fbl flies) that allows us to continuously monitor the modeled disease in the brain. In tim-fbl flies, downregulation of fumble, the Drosophila PanK homologue in the cells containing a circadian clock results in characteristic features of PKAN such as developmental lethality, hypersensitivity to oxidative stress, and diminished life span. Despite quasi-normal circadian transcriptional rhythms, tim-fbl flies display brain-specific aberrant circadian locomotor rhythms, and a unique transcriptional signature. Comparison with expression data from flies exposed to paraquat demonstrates that, as previously suggested, pathways others than oxidative stress are affected by PANK downregulation. Surprisingly we found a significant decrease in the expression of key components of the photoreceptor recycling pathways, which could lead to retinal degeneration, a hallmark of PKAN. Importantly, these defects are not accompanied by changes in structural components in eye genes suggesting that changes in gene expression in the eye precede and may cause the retinal degeneration. Indeed tim-fbl flies have diminished response to light transitions, and their altered day/night patterns of activity demonstrates defects in light perception. This suggest that retinal lesions are not solely due to oxidative stress and demonstrates a role for the transcriptional response to CoA deficiency underlying the defects observed in dPanK deficient flies. Moreover, in the present study we developed a new fly model that can be applied to other diseases and that allows the assessment of neurodegeneration in the brains of living flies.
Highlights
Pantothenate kinase enzymes (PanK)-associated neurodegeneration (PKAN, NBIA1, HSS, OMIM 234200) is a monogenic neurodegenerative motordisorder that results from diverse mutations of the human PanK2 gene (Zhou et al, 2001)
In order to do so, we utilized a publicly available UAS-RNAi transgene targeted against the endogenous Drosophila PanK2 homologue (dPanK) mRNA and the tim-gal4 driver to express it exclusively in circadian tissues
This combination of transgenes restricts the expression of the transgene to only tissues harboring a circadian clock
Summary
PanK-associated neurodegeneration (PKAN, NBIA1, HSS, OMIM 234200) is a monogenic neurodegenerative motordisorder that results from diverse mutations of the human PanK2 gene (Zhou et al, 2001). In PKAN, symptoms begin in childhood and progressively worsen resulting in a drastically reduced life span (Gregory et al, 2009) as well as retinal degeneration, a hallmark of the disease (Egan et al, 2005). The iron accumulation correlates with neural damage and mitochondrial lesions; the etiological link between PanK2-loss and the neurodegenerative phenotype is not well understood. The PanK2 gene is one of four PanK genes in mammals, and diverse loss-of-function mutations in this gene in humans result in PKAN (Gregory and Hayflick, 2005; Kotzbauer et al, 2005; Leonardi et al, 2007). The mutant mice did not suffer from movement disorders nor did these mice show signs of neurodegeneration, implying that the other PanK genes may compensate for PanK2 loss in mice (Leonardi et al, 2007)
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