title: Mechanisms of granulin deficiency: lessons from cellular and animal models.
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.
authors.affiliation: Neurodegenerative Brain Diseases Group, VIB Department of Molecular Genetics, University of Antwerp-CDE, Universiteitsplein 1, Antwerp, 2610, Belgium.
authors.forename: Gernot
authors.initials: G
authors.lastname: Kleinberger
authors.forename: Anja
authors.initials: A
authors.lastname: Capell
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
mesh_terms: D000818:Animals; D002477:Cells / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000473:pathology*; D000077153:Progranulins; D015398:Signal Transduction
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins