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• W1992138269 endingPage "360" @default.
• W1992138269 startingPage "337" @default.
• W1992138269 abstract "The identification of causative mutations in the (pro)granulin gene (GRN) has been a major breakthrough in the research on frontotemporal dementia (FTD). So far, all FTD-associated GRN mutations are leading to neurodegeneration through a “loss-of-function” mechanism, encouraging researchers to develop a growing number of cellular and animal models for GRN deficiency. GRN is a multifunctional secreted growth factor, and loss of its function can affect different cellular processes. Besides loss-of-function (i.e., mostly premature termination codons) mutations, which cause GRN haploinsufficiency through reduction of GRN expression, FTD-associated GRN missense mutations have also been identified. Several of these missense mutations are predicted to increase the risk of developing neurodegenerative diseases through altering various key biological properties of GRN-like protein secretion, proteolytic processing, and neurite outgrowth. With the use of cellular and animal models for GRN deficiency, the portfolio of GRN functions has recently been extended to include functions in important biological processes like energy and protein homeostasis, inflammation as well as neuronal survival, neurite outgrowth, and branching. Furthermore, GRN-deficient animal models have been established and they are believed to be promising disease models as they show accelerated aging and recapitulate at least some neuropathological features of FTD. In this review, we summarize the current knowledge on the molecular mechanisms leading to GRN deficiency and the lessons we learned from the established cellular and animal models. Furthermore, we discuss how these insights might help in developing therapeutic strategies for GRN-associated FTD." @default.
• W1992138269 created "2016-06-24" @default.
• W1992138269 creator A5008355134 @default.
• W1992138269 creator A5039639102 @default.
• W1992138269 creator A5043404109 @default.
• W1992138269 creator A5065084452 @default.
• W1992138269 date "2012-12-13" @default.
• W1992138269 modified "2023-10-17" @default.
• W1992138269 title "Mechanisms of Granulin Deficiency: Lessons from Cellular and Animal Models" @default.
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