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

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.

• Authors: Alice S Chen-Plotkin, Felix Geser, Joshua B Plotkin, Chris M Clark, Linda K Kwong, Wuxing Yuan, Murray Grossman, Vivianna M Van Deerlin, John Q Trojanowski, Virginia M-Y Lee
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 17 Issue 10 Pg. 1349-62 (May 15 2008) ISSN: 1460-2083 [Electronic] England
• PMID: 18223198 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Intercellular Signaling Peptides and Proteins
• Progranulins

Topics

• Aged
• Brain (physiopathology)
• Case-Control Studies
• Cluster Analysis
• Dementia (genetics, physiopathology)
• Female
• Gene Expression Profiling
• Gene Expression Regulation
• Genetic Variation
• Humans
• Intercellular Signaling Peptides and Proteins (genetics, metabolism)
• Male
• Middle Aged
• Mutation
• Neurodegenerative Diseases (genetics)
• Oligonucleotide Array Sequence Analysis
• Progranulins
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction