title: Potential mechanisms of progranulin-deficient FTLD.
abstract: Frontotemporal lobar dementia (FTLD) is the most common cause of dementia in patients younger than 60 years of age, and causes progressive neurodegeneration of the frontal and temporal lobes usually accompanied by devastating changes in language or behavior in affected individuals. Mutations in the progranulin (GRN) gene account for a significant fraction of familial FTLD, and in the vast majority of cases, these mutations lead to reduced expression of progranulin via nonsense-mediated mRNA decay. Progranulin is a secreted glycoprotein that regulates a diverse range of cellular functions including cell proliferation, cell migration, and inflammation. Recent fundamental discoveries about progranulin biology, including the findings that sortilin and tumor necrosis factor receptor (TNFR) are high affinity progranulin receptors, are beginning to shed light on the mechanism(s) by which progranulin deficiency causes FTLD. This review will explore how alterations in basic cellular functions due to PGRN deficiency, both intrinsic and extrinsic to neurons, might lead to the development of FTLD.
authors: Memory and Aging Center, University of California, San Francisco, 350 Parnassus Avenue, Suite 905, San Francisco, CA 94143, USA. michael.ward@ucsf.edu
authors: Michael Emmerson
authors: ME
authors: Ward
authors: Bruce L
authors: BL
authors: Miller
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology*; D006801:Humans; D007249:Inflammation / Q000473:pathology / Q000503:physiopathology; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D059365:Nonsense Mediated mRNA Decay; D000077153:Progranulins; D011956:Receptors, Cell Surface / Q000378:metabolism; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D004268:DNA-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D011956:Receptors, Cell Surface; D000099183:Sortilin; C492314:GRN protein, human