NDLI: Mechanisms of Granulin Deficiency: Lessons from Cellular and Animal Models

Content Provider	Springer Nature Link
Author	Kleinberger, Gert Capell, Anja Haass, Christian Van Broeckhoven, Christine
Copyright Year	2012
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.
Starting Page	337
Ending Page	360
Page Count	24
File Format	PDF
ISSN	08937648
Journal	Molecular Neurobiology
Volume Number	47
Issue Number	1
e-ISSN	15591182
Language	English
Publisher	Humana Press Inc
Publisher Date	2012-12-13
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Neurodegeneration FTD Progranulin Granulins Cellular model Animal model Growth factor Therapy Neurosciences Neurobiology Cell Biology Neurology
Content Type	Text
Resource Type	Article
Subject	Neurology Cellular and Molecular Neuroscience

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Mechanisms of Granulin Deficiency: Lessons from Cellular and Animal Models

Mechanisms of Granulin Deficiency: Lessons from Cellular and Animal Models

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