title: Progranulin reduction is associated with increased tau phosphorylation in P301L tau transgenic mice.
abstract: Granulin (GRN) mutations have been identified in familial frontotemporal lobar degeneration patients with ubiquitin pathology. GRN transcript haploinsufficiency is proposed as a disease mechanism that leads to the loss of functional progranulin (PGRN) protein. Thus, these mutations are strongly involved in frontotemporal lobar degeneration pathogenesis. Moreover, recent findings indicate that GRN mutations are associated with other neurodegenerative disorders with tau pathology, including Alzheimer disease and corticobasal degeneration. To investigate the potential influence of a decline in PGRN protein on tau accumulation, P301L tau transgenic mice were interbred with GRN-deficient mice, producing P301L tau transgenic mice harboring the GRN hemizygote. Brains were collected from 13- and 19-month-old mice, and sequential extraction of proteins, immunoblotting, and immunohistochemical analyses were performed. Immunoblotting analysis revealed that tau phosphorylation was accelerated in the Tris-saline soluble fraction of 13-month-old and in the sarkosyl-insoluble fraction of 19-month-old P301L tau/GRN hemizygotes compared with those in fractions from P301L tau transgenic mice. Activity of cyclin-dependent kinases was also upregulated in the brains of P301L tau/GRN hemizygote mice. Although the mechanisms involved in these findings remain unknown, our data suggest that a reduction in PGRN protein might contribute to phosphorylation and intraneuronal accumulation of tau.
authors.affiliation: From the Dementia Research Project (MH, TA, HA), Department of Neuropathology and Cell Biology (MM-S, MH), and Histology Center (HK), Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo; Department of Neuropsychiatry, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki (TA); and Department of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo (TM, MN), Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Hosokawa
authors.forename: Tetsuaki
authors.initials: T
authors.lastname: Arai
authors.forename: Masami
authors.initials: M
authors.lastname: Masuda-Suzukake
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kondo
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsuwaki
authors.forename: Masugi
authors.initials: M
authors.lastname: Nishihara
authors.forename: Masato
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Akiyama
mesh_terms: D000367:Age Factors; D000818:Animals; D001921:Brain / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007532:Isoleucine / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation / Q000235:genetics; D000077153:Progranulins; D011392:Proline / Q000235:genetics; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D016875:tau Proteins; D007532:Isoleucine; D011392:Proline; D018844:Cyclin-Dependent Kinases; D020929:Mitogen-Activated Protein Kinase Kinases