title: 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.affiliation: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Alice S
authors.initials: AS
authors.lastname: Chen-Plotkin
authors.forename: Felix
authors.initials: F
authors.lastname: Geser
authors.forename: Joshua B
authors.initials: JB
authors.lastname: Plotkin
authors.forename: Chris M
authors.initials: CM
authors.lastname: Clark
authors.forename: Linda K
authors.initials: LK
authors.lastname: Kwong
authors.forename: Wuxing
authors.initials: W
authors.lastname: Yuan
authors.forename: Murray
authors.initials: M
authors.lastname: Grossman
authors.forename: Vivianna M
authors.initials: VM
authors.lastname: Van Deerlin
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
mesh_terms: D000368:Aged; D001921:Brain / Q000503:physiopathology; D016022:Case-Control Studies; D016000:Cluster Analysis; D003704:Dementia / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D014644:Genetic Variation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D000077153:Progranulins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins