Lipidomic and Transcriptomic Basis of Lysosomal Dysfunction in Progranulin Deficiency
Defective lysosomal function defines many neurodegenerative diseases, such as neuronal ceroid lipofuscinoses (NCL) and Niemann-Pick type C (NPC), and is implicated in Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD-TDP) with progranulin (PGRN) deficiency. Here, we show that PGRN...
Main Authors: | , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2017-09-01
|
Series: | Cell Reports |
Subjects: | |
Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124717311816 |
id |
doaj-a8b5570d8446427886cab7bf1d9791a5 |
---|---|
record_format |
Article |
spelling |
doaj-a8b5570d8446427886cab7bf1d9791a52020-11-25T00:16:20ZengElsevierCell Reports2211-12472017-09-0120112565257410.1016/j.celrep.2017.08.056Lipidomic and Transcriptomic Basis of Lysosomal Dysfunction in Progranulin DeficiencyBret M. Evers0Carlos Rodriguez-Navas1Rachel J. Tesla2Janine Prange-Kiel3Catherine R. Wasser4Kyoung Shin Yoo5Jeffrey McDonald6Basar Cenik7Thomas A. Ravenscroft8Florian Plattner9Rosa Rademakers10Gang Yu11Charles L. White, III12Joachim Herz13Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USACenter for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USACenter for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USACenter for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USACenter for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USACenter for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USADepartment of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USADepartment of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USADepartment of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USACenter for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USADepartment of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USACenter for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USADepartment of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USACenter for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USADefective lysosomal function defines many neurodegenerative diseases, such as neuronal ceroid lipofuscinoses (NCL) and Niemann-Pick type C (NPC), and is implicated in Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD-TDP) with progranulin (PGRN) deficiency. Here, we show that PGRN is involved in lysosomal homeostasis and lipid metabolism. PGRN deficiency alters lysosome abundance and morphology in mouse neurons. Using an unbiased lipidomic approach, we found that brain lipid composition in humans and mice with PGRN deficiency shows disease-specific differences that distinguish them from normal and other pathologic groups. PGRN loss leads to an accumulation of polyunsaturated triacylglycerides, as well as a reduction of diacylglycerides and phosphatidylserines in fibroblast and enriched lysosome lipidomes. Transcriptomic analysis of PGRN-deficient mouse brains revealed distinct expression patterns of lysosomal, immune-related, and lipid metabolic genes. These findings have implications for the pathogenesis of FTLD-TDP due to PGRN deficiency and suggest lysosomal dysfunction as an underlying mechanism.http://www.sciencedirect.com/science/article/pii/S2211124717311816neurodegenerationAlzheimer’s diseasefrontotemporal lobar degenerationlipidslipidomicstranscriptomicslysosomelysosomal storage disordersneuronal ceroid lipofuscinoses |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Bret M. Evers Carlos Rodriguez-Navas Rachel J. Tesla Janine Prange-Kiel Catherine R. Wasser Kyoung Shin Yoo Jeffrey McDonald Basar Cenik Thomas A. Ravenscroft Florian Plattner Rosa Rademakers Gang Yu Charles L. White, III Joachim Herz |
spellingShingle |
Bret M. Evers Carlos Rodriguez-Navas Rachel J. Tesla Janine Prange-Kiel Catherine R. Wasser Kyoung Shin Yoo Jeffrey McDonald Basar Cenik Thomas A. Ravenscroft Florian Plattner Rosa Rademakers Gang Yu Charles L. White, III Joachim Herz Lipidomic and Transcriptomic Basis of Lysosomal Dysfunction in Progranulin Deficiency Cell Reports neurodegeneration Alzheimer’s disease frontotemporal lobar degeneration lipids lipidomics transcriptomics lysosome lysosomal storage disorders neuronal ceroid lipofuscinoses |
author_facet |
Bret M. Evers Carlos Rodriguez-Navas Rachel J. Tesla Janine Prange-Kiel Catherine R. Wasser Kyoung Shin Yoo Jeffrey McDonald Basar Cenik Thomas A. Ravenscroft Florian Plattner Rosa Rademakers Gang Yu Charles L. White, III Joachim Herz |
author_sort |
Bret M. Evers |
title |
Lipidomic and Transcriptomic Basis of Lysosomal Dysfunction in Progranulin Deficiency |
title_short |
Lipidomic and Transcriptomic Basis of Lysosomal Dysfunction in Progranulin Deficiency |
title_full |
Lipidomic and Transcriptomic Basis of Lysosomal Dysfunction in Progranulin Deficiency |
title_fullStr |
Lipidomic and Transcriptomic Basis of Lysosomal Dysfunction in Progranulin Deficiency |
title_full_unstemmed |
Lipidomic and Transcriptomic Basis of Lysosomal Dysfunction in Progranulin Deficiency |
title_sort |
lipidomic and transcriptomic basis of lysosomal dysfunction in progranulin deficiency |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2017-09-01 |
description |
Defective lysosomal function defines many neurodegenerative diseases, such as neuronal ceroid lipofuscinoses (NCL) and Niemann-Pick type C (NPC), and is implicated in Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD-TDP) with progranulin (PGRN) deficiency. Here, we show that PGRN is involved in lysosomal homeostasis and lipid metabolism. PGRN deficiency alters lysosome abundance and morphology in mouse neurons. Using an unbiased lipidomic approach, we found that brain lipid composition in humans and mice with PGRN deficiency shows disease-specific differences that distinguish them from normal and other pathologic groups. PGRN loss leads to an accumulation of polyunsaturated triacylglycerides, as well as a reduction of diacylglycerides and phosphatidylserines in fibroblast and enriched lysosome lipidomes. Transcriptomic analysis of PGRN-deficient mouse brains revealed distinct expression patterns of lysosomal, immune-related, and lipid metabolic genes. These findings have implications for the pathogenesis of FTLD-TDP due to PGRN deficiency and suggest lysosomal dysfunction as an underlying mechanism. |
topic |
neurodegeneration Alzheimer’s disease frontotemporal lobar degeneration lipids lipidomics transcriptomics lysosome lysosomal storage disorders neuronal ceroid lipofuscinoses |
url |
http://www.sciencedirect.com/science/article/pii/S2211124717311816 |
work_keys_str_mv |
AT bretmevers lipidomicandtranscriptomicbasisoflysosomaldysfunctioninprogranulindeficiency AT carlosrodrigueznavas lipidomicandtranscriptomicbasisoflysosomaldysfunctioninprogranulindeficiency AT racheljtesla lipidomicandtranscriptomicbasisoflysosomaldysfunctioninprogranulindeficiency AT janineprangekiel lipidomicandtranscriptomicbasisoflysosomaldysfunctioninprogranulindeficiency AT catherinerwasser lipidomicandtranscriptomicbasisoflysosomaldysfunctioninprogranulindeficiency AT kyoungshinyoo lipidomicandtranscriptomicbasisoflysosomaldysfunctioninprogranulindeficiency AT jeffreymcdonald lipidomicandtranscriptomicbasisoflysosomaldysfunctioninprogranulindeficiency AT basarcenik lipidomicandtranscriptomicbasisoflysosomaldysfunctioninprogranulindeficiency AT thomasaravenscroft lipidomicandtranscriptomicbasisoflysosomaldysfunctioninprogranulindeficiency AT florianplattner lipidomicandtranscriptomicbasisoflysosomaldysfunctioninprogranulindeficiency AT rosarademakers lipidomicandtranscriptomicbasisoflysosomaldysfunctioninprogranulindeficiency AT gangyu lipidomicandtranscriptomicbasisoflysosomaldysfunctioninprogranulindeficiency AT charleslwhiteiii lipidomicandtranscriptomicbasisoflysosomaldysfunctioninprogranulindeficiency AT joachimherz lipidomicandtranscriptomicbasisoflysosomaldysfunctioninprogranulindeficiency |
_version_ |
1725383209551659008 |