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.

Looking for Neuroimaging Markers in Frontotemporal Lobar Degeneration Clinical Trials: A Multi-Voxel Pattern Analysis Study in Granulin Disease

“…FTD-GRN+, frontotemporal dementia carrying Granulin mutation; aGRN+, asymptomatic carriers of Granulin mutation. molecular pathway [6,17,43]. GRN mutations lead to a homogeneous FTD-TDP pathology and give the opportunity to unravel FTD from asymptomatic to symptomatic stages [17,20,44].…”

Progranulin Transcripts with Short and Long 5′ Untranslated Regions (UTRs) Are Differentially Expressed via Posttranscriptional and Translational Repression

“…Enhanced expression of GRN is observed upon lysosomal stress, inflammation, wound healing, and tumorigenesis, whereas reduced levels of GRN are associated with a significantly enhanced risk for FTLD-TDP (7). Expression of GRN is controlled on several levels.…”

“…The risk for FTLD-TDP is increased dramatically in patients with a haploinsufficiency for progranulin (GRN) (5,6). Genetic linkage analysis and exome sequencing identified a large number of non-sense mutations that all lead to GRN haploinsufficiency (7). In addition, missense mutations were also found (8 -10), which can lead to cytoplasmic missorting of GRN because of a dysfunctional signal peptide or to misfolding and, consequently, to a reduction of GRN secretion (7,11,12).…”

“…Genetic linkage analysis and exome sequencing identified a large number of non-sense mutations that all lead to GRN haploinsufficiency (7). In addition, missense mutations were also found (8 -10), which can lead to cytoplasmic missorting of GRN because of a dysfunctional signal peptide or to misfolding and, consequently, to a reduction of GRN secretion (7,11,12). Therefore, all FTLD-TDP-associated GRN mutations result in reduced GRN levels.…”

P1‐196: Frontotemporal Dementia and Psychiatric Illness: Emerging Clinical and Biological Links in Gene Carriers

“…While the mechanisms by which FTDassociated mutations cause disease are still being determined, it is clear that they disrupt cell function in ways that can cause subtle structural and functional changes. [37][38][39][40][41][42][43] Mutationbased animal models of FTD have demonstrated subtle morphological changes in neurons, such as decreased synaptic density, altered spine morphology, and altered synaptic vesicle content, 40,41,44,45 as well as changes in physiological functions, such as excitatory postsynaptic potentials 41,44 and long-term potentiation. 45 These findings can be demonstrated in mice with behavioral abnormalities, such as anxiety and altered social interaction, months before neuropathological abnormalities develop.…”