Cited by 135Amyotrophic Lateral Sclerosis ResearchAlzheimer's disease research and treatmentsDementia and Cognitive Impairment Research

Variations in the progranulin gene affect global gene expression in frontotemporal lobar degeneration

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Chen-Plotkin, Alice S., Geser, Felix, Plotkin, Joshua B., Clark, Chris M., Kwong, Linda K., Yuan, Wuxing, Grossman, Murray, Van Deerlin, Vivianna M. +2 more·2008·Human Molecular Genetics

Abstract

Frontotemporal lobar degeneration is a fatal neurodegenerative disease that results in progressive decline in behavior, executive function and sometimes language. Disease mechanisms remain poorly understood. Recently, however, the DNA- and RNA-binding protein TDP-43 has been identified as the major protein present in the hallmark inclusion bodies of frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U), suggesting a role for transcriptional dysregulation in FTLD-U pathophysiology. Using the Affymetrix U133A microarray platform, we profiled global gene expression in both histopathologically affected and unaffected areas of human FTLD-U brains. We then characterized differential gene expression with biological pathway analyses, cluster and principal component analyses, and subgroup analyses based on brain region and progranulin (GRN) gene status. Comparing 17 FTLD-U brains to 11 controls, we identified 414 upregulated and 210 downregulated genes in frontal cortex (P-value < 0.001). Moreover, cluster and principal component analyses revealed that samples with mutations or possibly pathogenic variations in the GRN gene (GRN+, 7/17) had an expression signature that was distinct from both normal controls and FTLD-U samples lacking GRN gene variations (GRN-, 10/17). Within the subgroup of GRN+ FTLD-U, we found >1300 dysregulated genes in frontal cortex (P-value < 0.001), many participating in pathways uniquely dysregulated in the GRN+ cases. Our findings demonstrate a distinct molecular phenotype for GRN+ FTLD-U, not readily apparent on clinical or histopathological examination, suggesting distinct pathophysiological mechanisms for GRN+ and GRN- subtypes of FTLD-U. In addition, these data from a large number of human brains provide a valuable resource for future testing of disease hypotheses.

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Crossref · 10.1093/hmg/ddn023

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  • In FTD, two studies re-analysed published transcriptome data and discovered a role for WNT signalling in GRN-mediated FTD.

    “In FTD, two studies re-analysed published transcriptome data139 to discover a role for WNT signalling in GRN-mediated FTD153,154.”
  • In FTD, transcriptional signatures related to differential regional vulnerability have helped identify modulators of neurodegeneration.

    “In FTD, transcriptional signatures related to differential regional vulnerability have helped to identify modulators of neurodegeneration.”
  • A second FTD study comparing post-mortem tissue from GRN mutation carriers, sporadic FTD patients, and controls identified a diminishing hierarchy of susceptibility to FTD.

    “The second study139 compared post-mortem tissue from patients with FTD harbouring dominant mutations in the pro-granulin (GRN) gene, patients who had FTD but who did not have a known family history or mutations, and control individuals. This study also leveraged regional vulnerability by comparing transcriptome profiles in the frontal cortex, hippocampus and cerebellum, identifying a diminishing”
  • GRN-positive FTD individuals were transcriptomically distinct from those with sporadic FTD.

    “The findings demonstrated that GRN-positive individuals were a transcriptomically distinct group from those with sporadic FTD139.”

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Authors
Chen-Plotkin, A. S., Geser, F., Plotkin, J. B., Clark, C. M., Kwong, L. K., Yuan, W., Grossman, M., Van Deerlin, V. M., Trojanowski, J. Q., & Lee, V. M.-Y.
Affiliations
University of Pennsylvania (US)
Corresponding author
Lee, Virginia M.-Y.
Venue
Human Molecular Genetics
Published
2008-01-25
Volume
17
Issue
10
Pages
1349-1362
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
OpenAlex
W2145817301
Cited by
135
References
65
Citations by year
2026: 2 · 2025: 2 · 2024: 9 · 2023: 16 · 2022: 8 · 2021: 8 · 2020: 6 · 2019: 6 · 2018: 16 · 2017: 8 · 2016: 4 · 2015: 1 · 2014: 11 · 2013: 5 · 2012: 8
FWCI
5.30
Type
journal article
Language
en
Open access
Locations
  • Human Molecular Genetics (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • University of Pennsylvania
  • National Institute on Aging (AG15116, AG-19724, P30AG010124, R01AG015116, P01AG017586, AG17586, AG-10124, AG023501, P01AG019724, P50AG023501)
  • National Institute of Neurological Disorders and Stroke (NS-44266, R01NS044266)
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
frontotemporal lobar degeneration, progranulin gene, GRN mutations, TDP-43, FTLD-U, gene expression profiling, transcriptional dysregulation, frontal cortex, molecular phenotypes, neurodegeneration, pathophysiology
MeSH terms
Progranulins, Aged, Brain, Dementia, Female, Gene Expression Regulation, Humans, Male, Middle Aged, Mutation, Genetic Variation, Signal Transduction, Cluster Analysis, Case-Control Studies, Neurodegenerative Diseases, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Intercellular Signaling Peptides and Proteins

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