Partial Tmem106b reduction does not correct abnormalities due to progranulin haploinsufficiency

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

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Article number32
JournalMolecular Neurodegeneration
Volume13
Issue number1
DOIs
StatePublished - Jun 22 2018

Fingerprint

Haploinsufficiency
Frontotemporal Dementia
Mutation
Brain
Lysosome-Associated Membrane Glycoproteins
Neuronal Ceroid-Lipofuscinoses
Lipofuscin
Genome-Wide Association Study
Glucuronidase
Lysosomes
Glycoproteins
Alleles
Pathology
Phenotype

Keywords

  • Frontotemporal dementia
  • Lysosome
  • Progranulin
  • TMEM106B

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Partial Tmem106b reduction does not correct abnormalities due to progranulin haploinsufficiency. / Arrant, Andrew E.; Nicholson, Alexandra M.; Zhou, Xiaolai; Rademakers, Rosa V; Roberson, Erik D.

In: Molecular Neurodegeneration, Vol. 13, No. 1, 32, 22.06.2018.

Research output: Contribution to journalArticle

Arrant, Andrew E. ; Nicholson, Alexandra M. ; Zhou, Xiaolai ; Rademakers, Rosa V ; Roberson, Erik D. / Partial Tmem106b reduction does not correct abnormalities due to progranulin haploinsufficiency. In: Molecular Neurodegeneration. 2018 ; Vol. 13, No. 1.
@article{867e7881f5b546d783e937b5d67ac850,
title = "Partial Tmem106b reduction does not correct abnormalities due to progranulin haploinsufficiency",
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.",
keywords = "Frontotemporal dementia, Lysosome, Progranulin, TMEM106B",
author = "Arrant, {Andrew E.} and Nicholson, {Alexandra M.} and Xiaolai Zhou and Rademakers, {Rosa V} and Roberson, {Erik D.}",
year = "2018",
month = "6",
day = "22",
doi = "10.1186/s13024-018-0264-6",
language = "English (US)",
volume = "13",
journal = "Molecular Neurodegeneration",
issn = "1750-1326",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - Partial Tmem106b reduction does not correct abnormalities due to progranulin haploinsufficiency

AU - Arrant, Andrew E.

AU - Nicholson, Alexandra M.

AU - Zhou, Xiaolai

AU - Rademakers, Rosa V

AU - Roberson, Erik D.

PY - 2018/6/22

Y1 - 2018/6/22

N2 - 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.

AB - 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.

KW - Frontotemporal dementia

KW - Lysosome

KW - Progranulin

KW - TMEM106B

UR - http://www.scopus.com/inward/record.url?scp=85048809647&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85048809647&partnerID=8YFLogxK

U2 - 10.1186/s13024-018-0264-6

DO - 10.1186/s13024-018-0264-6

M3 - Article

C2 - 29929528

AN - SCOPUS:85048809647

VL - 13

JO - Molecular Neurodegeneration

JF - Molecular Neurodegeneration

SN - 1750-1326

IS - 1

M1 - 32

ER -