The enigmatic roles of microglial versus neuronal progranulin in neurological disease.

Progranulin is an ancient, highly conserved gene that regu-lates cell division, survival, and migration across a widevariety of species. Until the publication of two papersshowing that mutations in a single copy of the human GRNgene was the cause of frontotemporal lobar dementia withubiquitinated TDP-43 inclusions(FTLD-TDP)[2, 5] in 2006,very little was known about the importance of progranulinwithin the central nervous system. These reports created astrong impetus to identify new mutations and to explore thecontributionofthisproteininbrainhealthanddisease.Within3 years of the ﬁrst publications, the Alzheimer Disease andFrontotemporal Dementia Mutation Database (http://www.molgen.ua.ac.be/FTDMutations/) has grown to encompass68 distinct GRN mutations in 218 families.In contrast to many neurodegenerative disorders wheremutations result in a toxic gain-of function, most of theGRN-dependent FTLD-TDPs are thought to be caused by aglobal decrease in the levels of expressed or secretedprogranulin. The vast majority of reported mutations leadto nonsense-mediated mRNA decay, a mechanism forelimination of mutant transcripts, resulting in complete lossof mRNA expression from one allele [7]. Although avariety of different mutations have been described, themost common genetic mutations result from prematureinsertion of stop codons or frame shifts, causing destructionof mRNA through nonsense-mediated decay. The prevail-ing wealth of mutations that have been recently discovered,all ascribed with a similar mode of action, have stronglysupported the hypothesis that GRN haploinsufﬁciencyresults in insufﬁcient GRN protein, leading to disease.Althoughalargenumberofmutationshavebeenidentiﬁedsince 2006, there have been a paucity of studies character-izing GRN expression in FTLD-TDP patients, and themechanisms describing the pathogenic loss of progranulinhave been developed primarily from studies of patient-derived lymphoblastoid cell lines. While these mechanismsclearlyshowtheeffectofthegeneticmutationsonproductionof the protein, there is a widespread variation in the ageof disease onset; some carriers with pathological GRNmutations remain cognitively unimpaired into their 70s. Twopublications in this issue of Acta Neuropathologica, one byChen-Plotkin et al. [4] and the other by Naphade et al. [6],on the dynamic regulation of progranulin in the CNS suggestthat the prevailing hypothesis of global GRN haploinsufﬁ-ciency leading to a loss of protein may be too simplistic anexplanation to completely account for development ofFTLD-TDP.The paper by Chen-Plotkin et al. [4] has ﬁlled anoticeable gap in the FTLD-TDP literature by providing adetailed comparison of regional progranulin expression inthe brains of affected patients that span 11 different GRNvariants, comparing expression in frontal and temporalcortex, 2 histopathologically involved regions, and theoccipital cortex and cerebellum, 2 spared regions, againstthe brains of both control patients and FTLD-TDP patientswithout GRN mutations. Similar to previous studies, theauthors reported a notable reduction in GRN transcripts inlymphoblastoid cell lines derived from the GRN mutationcarriers. However, when comparing levels of progranulintranscript between the normal controls and FTLD-TDPpatients with GRN mutations, they made the surprisingdiscovery that progranulin transcripts were not signiﬁcantlydecreased in any of the brain regions surveyed, andreported that the frontal cortex showed strongly elevatedlevels of GRN transcript compared with control. By