Abstract
BackgroundLoss of function mutations in progranulin (GRN) are a major cause of frontotemporal dementia (FTD). Progranulin is a secreted glycoprotein that localizes to lysosomes and is critical for proper lysosomal function. Heterozygous GRN mutation carriers develop FTD with TDP-43 pathology and exhibit signs of lysosomal dysfunction in the brain, with increased levels of lysosomal proteins and lipofuscin accumulation. Homozygous GRN mutation carriers develop neuronal ceroid lipofuscinosis (NCL), an earlier-onset lysosomal storage disorder caused by severe lysosomal dysfunction. Multiple genome-wide association studies have shown that risk of FTD in GRN mutation carriers is modified by polymorphisms in TMEM106B, which encodes a lysosomal membrane protein. Risk alleles of TMEM106B may increase TMEM106B levels through a variety of mechanisms. Brains from FTD patients with GRN mutations exhibit increased TMEM106B expression, and protective TMEM106B polymorphisms are associated with decreased TMEM106B expression. Together, these data raise the possibility that reduction of TMEM106B levels may protect against the pathogenic effects of progranulin haploinsufficiency.MethodsWe crossed Tmem106b+/− mice with Grn+/− mice, which model the progranulin haploinsufficiency of GRN mutation carriers and develop age-dependent social deficits and lysosomal abnormalities in the brain. We tested whether partial Tmem106b reduction could normalize the social deficits and lysosomal abnormalities of Grn+/− mice.ResultsPartial reduction of Tmem106b levels did not correct the social deficits of Grn+/− mice. Tmem106b reduction also failed to normalize most lysosomal abnormalities of Grn+/− mice, except for β-glucuronidase activity, which was suppressed by Tmem106b reduction and increased by progranulin insufficiency.ConclusionsThese data do not support the hypothesis that Tmem106b reduction protects against the pathogenic effects of progranulin haploinsufficiency, but do show that Tmem106b reduction normalizes some lysosomal phenotypes in Grn+/− mice.
Highlights
Loss of function mutations in progranulin (GRN) are a major cause of frontotemporal dementia (FTD)
TMEM106B was first identified as a genetic risk factor for FTD with TDP-43 pathology (FTD-TDP) when a Arrant et al Molecular Neurodegeneration (2018) 13:32 genome-wide association study found three single nucleotide polymorphisms (SNPs) associated with FTD-TDP risk in the region of chromosome 7 that contains TMEM106B [10]
Tmem106b reduction does not rescue the low social dominance phenotype of Grn+/− mice To test the hypothesis that Tmem106b reduction may rescue deficits induced by progranulin haploinsufficiency, we tested wild-type (Grn+/+:Tmem106b+/+), Grn+/−: Tmem106b+/+, and Grn+/−:Tmem106b+/− mice in the tube test for social dominance at age 11–12 months
Summary
Loss of function mutations in progranulin (GRN) are a major cause of frontotemporal dementia (FTD). Brains from FTD patients with GRN mutations exhibit increased TMEM106B expression, and protective TMEM106B polymorphisms are associated with decreased TMEM106B expression Together, these data raise the possibility that reduction of TMEM106B levels may protect against the pathogenic effects of progranulin haploinsufficiency. TMEM106B was first identified as a genetic risk factor for FTD with TDP-43 pathology (FTD-TDP) when a Arrant et al Molecular Neurodegeneration (2018) 13:32 genome-wide association study found three single nucleotide polymorphisms (SNPs) associated with FTD-TDP risk in the region of chromosome 7 that contains TMEM106B [10] Subsequent analyses identified these SNPs to be more strongly associated with FTD risk in individuals with GRN mutations [10], an observation that was replicated in several additional studies [11,12,13]. Many genetic studies show a clear relationship of TMEM106B and GRN in FTD pathogenesis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
