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Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2018

Open Access 01-12-2018 | Research article

Partial Tmem106b reduction does not correct abnormalities due to progranulin haploinsufficiency

Authors: Andrew E. Arrant, Alexandra M. Nicholson, Xiaolai Zhou, Rosa Rademakers, Erik D. Roberson

Published in: Molecular Neurodegeneration | Issue 1/2018

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Abstract

Background

Loss 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.

Methods

We 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.

Results

Partial 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.

Conclusions

These 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.
Appendix
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Metadata
Title
Partial Tmem106b reduction does not correct abnormalities due to progranulin haploinsufficiency
Authors
Andrew E. Arrant
Alexandra M. Nicholson
Xiaolai Zhou
Rosa Rademakers
Erik D. Roberson
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2018
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-018-0264-6

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