A new in vivo model of pantothenate kinase-associated neurodegeneration reveals a surprising role for transcriptional regulation in pathogenesis

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.

Mitochondrial iron and energetic dysfunction distinguish fibroblasts and induced neurons from pantothenate kinase-associated neurodegeneration patients

“…This effect was highlighted by the studies of PKAN disease models in flies and mice. These analyses revealed different types of CoA-deficiency related phenotype, such as the following: sterility ( Afshar et al, 2001 , Kuo et al, 2005 ); abnormal locomotor function, neurodegeneration, and reduced life span ( Bosveld et al, 2008 ); mitochondrial impairment ( Brunetti et al, 2012 , Rana et al, 2010 ); altered cytoskeleton function ( Siudeja et al, 2012 ); protein acetylation ( Siudeja et al, 2011 ); disrupted circadian locomotor patterns and a unique transcriptional signature ( Pandey et al, 2013 ). However, all of these investigations have not clarified the mechanism of one of the major features of the human disease, brain iron accumulation, which has not been reported neither in flies nor in mice ( Brunetti et al, 2012 , Rana et al, 2010 ).…”

Neurodegeneration with brain iron accumulation: update on pathogenic mechanisms

“…This piece of evidence reinforces and strengthen the direct connection between CoA metabolism and the neurodegenerative process of PKAN. Very recently an alternate drosophila model has been generated with exclusive suppression of fbl in tissues with circadian clock cells, that is eyes, fat and specific neural cells (Pandey et al, 2013). The phenotype of these flies recapitulated aspects observed in the flb1 hypomorphic animals, with increased sensitivity to oxidative stress, developmental lethality, and shorter lifespan; the transcriptome analysis revealed features partially overlapping with those observed in flies exposed to paraquat, that is in pro-oxidant conditions, but also a specific signature with perturbed expression of genes involved in mitochondrial pathways, cytoskeleton assembly, cell surface receptor signaling, and eye pigment biosynthesis, that could be particularly relevant in the development of retinal degeneration.…”

Investigating population‐scale allelic differential expression in wild populations of Oithona similis (Cyclopoida, Claus, 1866)

“…, for each locus between each pair of populations i and the median pairwise-F ST was retained to measure the genomic differentiation between each population. A Mantel test was performed to test for isolation-by-distance between median pairwise-F ST and geographic Euclidean distances using vegan v2.5-2 (Oksanen et al 2018) and geosphere v1.5-7 (Hijmans, 2017) R packages. The pcadapt R package v4.0.2 (Luu, Bazin, & Blum, 2017) was used to detect selection among populations from the B-allele frequency matrix.…”