FTLD-TDP with and without GRN mutations cause different patterns of CA1 pathology

Qinwen Mao*, Xiaojing Zheng, Tamar Gefen, Emily Rogalski, Callen L. Spencer, Rosa Rademakers, Angela J. Fought, Missia Kohler, Sandra Weintraub, Haibin Xia, Marek Marsel Mesulam, Eileen H. Bigio

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Heterozygous loss-of-function mutations in the GRN gene lead to progranulin (PGRN) haploinsufficiency and cause frontotemporal lobar degeneration with TDP-43 pathology type A (FTLD-TDP type A). PGRN is a highly conserved, secreted glycoprotein and functions in the central nervous system as a key modulator of microglial function. Hence, altered microglial function caused by PGRN deficiency may be tied to the pathogenesis of FTLD-TDP. Our previous studies showed that haploinsufficiency of GRN mutations extends to microglial PGRN expression in the hippocampal CA1 region. In this study, we found that the CA1 sector was associated with less neuronal loss and more frequent TDP-43 inclusions in FTLD-TDP type A cases with GRN mutations than in sporadic cases. In addition, the CA1 region in GRN mutation cases contained more rod-like microglia, which also had reduced PGRN expression. These findings suggest that the profile of TDP-43 inclusions, neuronal number, and microgliosis in the CA1 sector of FTLD-TDP type A cases may be influenced by GRN gene expression status.

Original languageEnglish (US)
Pages (from-to)844-853
Number of pages10
JournalJournal of neuropathology and experimental neurology
Volume78
Issue number9
DOIs
StatePublished - Sep 1 2019

Keywords

  • Frontotemporal lobar degeneration
  • Hippocampal sclerosis
  • Microglia
  • Neuroinflammation
  • Progranulin
  • TAR DNA-binding protein 43

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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