Broad spectrum metabolomics for detection of abnormal metabolic pathways in a mouse model for retinitis pigmentosa

• Published in: Experimental eye research Vol. 184; pp. 135 - 145
• Main Authors: Weiss, Ellen R., Osawa, Shoji, Xiong, Yubin, Dhungana, Suraj, Carlson, James, McRitchie, Susan, Fennell, Timothy R.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.07.2019
• Subjects: Animals; Chromatography, High Pressure Liquid; Deoxynucleotide; Disease Models, Animal; Mass Spectrometry; Metabolic Networks and Pathways - physiology; Metabolome - physiology; Metabolomics; Mice; Mice, Inbred C57BL; Nitric oxide; Nitrosamines - metabolism; Purine Nucleotides - metabolism; Pyrimidines - metabolism; Retinal degeneration; Retinitis Pigmentosa - metabolism; UPLC-TOF-MS; Retinal degeneration; UPLC-TOF-MS; Metabolomics; Deoxynucleotide; Nitric oxide
• ISSN: 0014-4835; 1096-0007
• DOI: 10.1016/j.exer.2019.03.007

Retinitis pigmentosa (RP) is a degenerative disease of the retina that affects approximately 1 million people worldwide. There are multiple genetic causes of this disease, for which, at present, there are no effective therapeutic strategies. In the present report, we utilized broad spectrum metabolomics to identify perturbations in the metabolism of the rd10 mouse, a genetic model for RP that contains a mutation in Pde6β. These data provide novel insights into mechanisms that are potentially critical for retinal degeneration. C57BL/6J and rd10 mice were raised in cyclic light followed by either light or dark adaptation at postnatal day (P) 18, an early stage in the degeneration process. Mice raised entirely in the dark until P18 were also evaluated. After euthanasia, retinas were removed and extracted for analysis by ultra-performance liquid chromatography-time of flight-mass spectrometry (UPLC-QTOF-MS). Compared to wild type mice, rd10 mice raised in cyclic light or in complete darkness demonstrate significant alterations in retinal pyrimidine and purine nucleotide metabolism, potentially disrupting deoxynucleotide pools necessary for mitochondrial DNA replication. Other metabolites that demonstrate significant increases are the Coenzyme A intermediate, 4′-phosphopantothenate, and acylcarnitines. The changes in these metabolites, identified for the first time in a model of RP, are highly likely to disrupt normal energy metabolism. High levels of nitrosoproline were also detected in rd10 retinas relative to those from wild type mice. These results suggest that nitrosative stress may be involved in retinal degeneration in this mouse model. •First use of broad spectrum metabolomics to identify metabolic perturbations in a mouse model for retinitis pigmentosa.•Differences in metabolite profiles were identified between wild type and rd10 mice raised in cyclic light or in the dark.•Pathways found to be most affected involved purine and pyrimidine deoxynucleotides.•Elevated levels of nitrosoproline suggest NO plays an important role in the degeneration program in rd10 mice.•These studies provide novel insights into retinal degeneration pathways that may lead to novel drug development.