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Progranulin deficiency is associated with neurodegeneration in humans and in mice. The mechanisms likely involve progranulin-promoted removal of protein waste via autophagy. We performed a deep proteomic screen of the pre-frontal cortex in aged (13–15 months) female progranulin-deficient mice (GRN−/−) and mice with inducible neuron-specific overexpression of progranulin (SLICK-GRN-OE) versus the respective control mice. Proteins were extracted and analyzed per liquid chromatography/mass spectrometry (LC/MS) on a Thermo Scientific™ Q Exactive Plus equipped with an ultra-high performance liquid chromatography unit and a Nanospray Flex Ion-Source. Full Scan MS-data were acquired using Xcalibur and raw files were analyzed using the proteomics software Max Quant. The mouse reference proteome set from uniprot (June 2015) was used to identify peptides and proteins. The DiB data file is a reduced MaxQuant output and includes peptide and protein identification, accession numbers, protein and gene names, sequence coverage and label free quantification (LFQ) values of each sample. Differences in protein expression in genotypes are presented in "Progranulin overexpression in sensory neurons attenuates neuropathic pain in mice: Role of autophagy" (C. Altmann, S. Hardt, C. Fischer, J. Heidler, H.Y. Lim, A. Haussler, B. Albuquerque, B. Zimmer, C. Moser, C. Behrends, F. Koentgen, I. Wittig, M.H. Schmidt, A.M. Clement, T. Deller, I. Tegeder, 2016) [1].
Loss-of-function mutations of progranulin are associated with frontotemporal dementia in humans, and its deficiency in mice is a model for this disease but with normal life expectancy and mild cognitive decline on aging. The present study shows that aging progranulin deficient mice develop progressive polydipsia and polyuria under standard housing conditions starting at middle age (6-9 months). They showed high water licking behavior and doubling of the normal daily drinking volume, associated with increased daily urine output and a decrease of urine osmolality, all maintained during water restriction. Creatinine clearance, urine urea, urine albumin and glucose were normal. Hence, there were no signs of osmotic diuresis or overt renal disease, other than a concentrating defect. In line, the kidney morphology and histology revealed a 50% increase of the kidney weight, kidney enlargement, mild infiltrations of the medulla with pro-inflammatory cells, widening of tubules but no overt signs of a glomerular or tubular pathology. Plasma vasopressin levels were on average about 3-fold higher than normal levels, suggesting that the water loss resulted from unresponsiveness of the collecting tubules towards vasopressin, and indeed aquaporin-2 immunofluorescence in collecting tubules was diminished, whereas renal and hypothalamic vasopressin were increased, the latter in spite of substantial astrogliosis in the hypothalamus. The data suggest that progranulin deficiency causes nephrogenic diabetes insipidus in mice during aging. Possibly, polydipsia in affected patients - eventually interpreted as psychogenic polydipsia - may point to a similar concentrating defect.