Progranulin Reduction Is Associated With Increased Tau Phosphorylation in P301L Tau Transgenic Mice. Issue 2 (February 2015)

• Record Type: Journal Article
• Authors: Hosokawa, Masato; Arai, Tetsuaki; Masuda-Suzukake, Masami; Kondo, Hiromi; Matsuwaki, Takashi; Nishihara, Masugi; Hasegawa, Masato; Akiyama, Haruhiko
• Is Part Of: Journal of neuropathology and experimental neurology. Volume 74:Issue 2(2015:Feb.)
• Publication Date: 2015-02
• Subjects: Neurology -- Diseases -- Periodicals; Neurology -- Diseases -- Physiopathology -- Periodicals; 616.8047
• DOI: 10.1097/NEN.0000000000000158
• Languages: English
• ISSNs: 0022-3069

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Abstract</title> <p>Granulin (<italic>GRN</italic>) mutations have been identified in familial frontotemporal lobar degeneration patients with ubiquitin pathology. <italic>GRN</italic> 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 <italic>GRN</italic> 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 <italic>GRN</italic>-deficient mice, producing P301L tau transgenic mice harboring the <italic>GRN</italic> 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/<italic>GRN</italic> 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/<italic>GRN</italic> 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.</p> </sec> </abstract>