Transcriptomic Approach to Lesch-Nyhan Disease

Dauphinot, Luce; Mockel, Lionel; Cahu, Julie; Jinnah, Hyder A.; Ledroit, Morgan; Potier, Marie‐Claude; Ceballos-Picot, Irène

doi:10.1080/15257770.2014.880477

Cited by 8 publications

(7 citation statements)

References 32 publications

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“…4C). This difference can be attributed to the fact that LND cells rely primarily on the de novo pathway to meet intracellular purine demand (13,35). Thus, LND cells provide support to justify our hypothesis that purinosome formation correlates with enhanced reliance on the de novo purine biosynthetic pathway.…”

Section: Discussionsupporting

confidence: 55%

Purinosome formation as a function of the cell cycle

Chan¹,

Zhao

Pugh

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The de novo purine biosynthetic pathway relies on six enzymes to catalyze the conversion of phosphoribosylpyrophosphate to inosine 5′-monophosphate. Under purine-depleted conditions, these enzymes form a multienzyme complex known as the purinosome. Previous studies have revealed the spatial organization and importance of the purinosome within mammalian cancer cells. In this study, time-lapse fluorescence microscopy was used to investigate the cell cycle dependency on purinosome formation in two cell models. Results in HeLa cells under purine-depleted conditions demonstrated a significantly higher number of cells with purinosomes in the G 1 phase, which was further confirmed by cell synchronization. HGPRT-deficient fibroblast cells also exhibited the greatest purinosome formation in the G 1 phase; however, elevated levels of purinosomes were also observed in the S and G 2 /M phases. The observed variation in cell cycle-dependent purinosome formation between the two cell models tested can be attributed to differences in purine biosynthetic mechanisms. Our results demonstrate that purinosome formation is closely related to the cell cycle.

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Section: Discussionsupporting

confidence: 55%

Purinosome formation as a function of the cell cycle

Chan¹,

Zhao

Pugh

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Second, protein synthesis is among the most sensitive of all cellular processes to ATP deficits [58, 59]. In fact, HGprt − cells tend to grow more slowly than their HGprt-competent counterparts in culture,[25, 48] and prior transcriptomic studies of HGprt-deficient cells have pointed to abnormalities of cell cycling [60]. Thus when purines may be limiting during cell division, cells may down-regulate protein expression to conserve energy and purine nucleotides.…”

Section: Discussionmentioning

confidence: 99%

“…There are no prior proteomic studies of HGprt-deficient cells for comparisons with the current studies, but there are several published transcriptomic studies involving mouse MN9D neuroblastoma cells [26], human NT2 neuroblastoma cells [43], human SH-SY5Y neuroblastoma cells [27], mouse ESD3 embryonic stem cells [30], and human fibroblasts [60]. A common finding in all of these studies was an unexpectedly broad array of gene expression abnormalities.…”

Section: Discussionmentioning

confidence: 99%

Consequences of impaired purine recycling on the proteome in a cellular model of Lesch–Nyhan disease

Dammer

Göttle

Duong

et al. 2015

Molecular Genetics and Metabolism

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The importance of specific pathways of purine metabolism for normal brain function is highlighted by several inherited disorders, such as Lesch-Nyhan disease (LND). In this disorder, deficiency of the purine recycling enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGprt), causes severe neurological and behavioral abnormalities. Despite many years of research, the mechanisms linking the defect in purine recycling to the neurobehavioral abnormalities remain unclear. In the current studies, an unbiased approach to the identification of potential mechanisms was undertaken by examining changes in protein expression in a model of HGprt deficiency based on the dopaminergic rat PC6-3 line, before and after differentiation with nerve growth factor (NGF). Protein expression profiles of 5 mutant sublines carrying different mutations affecting HGprt enzyme activity were compared to the HGprt-competent parent line using the method of stable isotopic labeling by amino acids in cell culture (SILAC) followed by denaturing gel electrophoresis with liquid chromatography and tandem mass spectrometry (LC-MS/MS) of tryptic digests, and subsequent identification of affected biochemical pathways using the Database for Annotation, Visualization and Integrated Discovery (DAVID) functional annotation chart analysis. The results demonstrate that HGprt deficiency causes broad changes in protein expression that depend on whether the cells are differentiated or not. Several of the pathways identified reflect predictable consequences of defective purine recycling. Other pathways were not anticipated, disclosing previously unknown connections with purine metabolism and novel insights into the pathogenesis of LND.

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“…This has been particularly notable in the field of neurogenetics research (for examples, see [15–18, 62–68]). In this study, we used BioLayout Express 3D [21] to interrogate publicly available databases of genome-wide expression results in the mouse.…”

Section: Discussionmentioning

confidence: 99%

Analysis of gene expression in the nervous system identifies key genes and novel candidates for health and disease

et al. 2017

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The incidence of neurodegenerative diseases in the developed world has risen over the last century, concomitant with an increase in average human lifespan. A major challenge is therefore to identify genes that control neuronal health and viability with a view to enhancing neuronal health during ageing and reducing the burden of neurodegeneration. Analysis of gene expression data has recently been used to infer gene functions for a range of tissues from co-expression networks. We have now applied this approach to transcriptomic datasets from the mammalian nervous system available in the public domain. We have defined the genes critical for influencing neuronal health and disease in different neurological cell types and brain regions. The functional contribution of genes in each co-expression cluster was validated using human disease and knockout mouse phenotypes, pathways and gene ontology term annotation. Additionally a number of poorly annotated genes were implicated by this approach in nervous system function. Exploiting gene expression data available in the public domain allowed us to validate key nervous system genes and, importantly, to identify additional genes with minimal functional annotation but with the same expression pattern. These genes are thus novel candidates for a role in neurological health and disease and could now be further investigated to confirm their function and regulation during ageing and neurodegeneration.Electronic supplementary materialThe online version of this article (doi:10.1007/s10048-017-0509-5) contains supplementary material, which is available to authorized users.

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Transcriptomic Approach to Lesch-Nyhan Disease

Cited by 8 publications

References 32 publications

Purinosome formation as a function of the cell cycle

Purinosome formation as a function of the cell cycle

Consequences of impaired purine recycling on the proteome in a cellular model of Lesch–Nyhan disease

Analysis of gene expression in the nervous system identifies key genes and novel candidates for health and disease

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