Lipidomic and Transcriptomic Basis of Lysosomal Dysfunction in Progranulin Deficiency

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, Joachim Herz*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

86 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)2565-2574
Number of pages10
JournalCell reports
Issue number11
StatePublished - Sep 12 2017
Externally publishedYes


  • Alzheimer's disease
  • frontotemporal lobar degeneration
  • lipidomics
  • lipids
  • lysosomal storage disorders
  • lysosome
  • neurodegeneration
  • neuronal ceroid lipofuscinoses
  • transcriptomics

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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