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Published on: July 19, 2019
Microarray RNA expression analysis of cerebral white matter lesions reveals changes in multiple functional pathways
Julie E Simpson1, Ola Hosny, Stephen B Wharton
1Academic Units of Pathology, University of Sheffield, Sheffield, UK.
Background And Purpose:
White matter lesions (WML) in brain aging are linked to dementia and depression. Ischemia contributes to their pathogenesis but other mechanisms may contribute. We used RNA microarray analysis with functional pathway grouping as an unbiased approach to investigate evidence for additional pathogenetic mechanisms.
Methods:
WML were identified by MRI and pathology in brains donated to the Medical Research Council Cognitive Function and Ageing Study Cognitive Function and Aging Study. RNA was extracted to compare WML with nonlesional white matter samples from cases with lesions (WM[L]), and from cases with no lesions (WM[C]) using RNA microarray and pathway analysis. Functional pathways were validated for selected genes by quantitative real-time polymerase chain reaction and immunocytochemistry.
Results:
We identified 8 major pathways in which multiple genes showed altered RNA transcription (immune regulation, cell cycle, apoptosis, proteolysis, ion transport, cell structure, electron transport, metabolism) among 502 genes that were differentially expressed in WML compared to WM[C]. In WM[L], 409 genes were altered involving the same pathways. Genes selected to validate this microarray data all showed the expected changes in RNA levels and immunohistochemical expression of protein.
Conclusions:
WML represent areas with a complex molecular phenotype. From this and previous evidence, WML may arise through tissue ischemia but may also reflect the contribution of additional factors like blood-brain barrier dysfunction. Differential expression of genes in WM[L] compared to WM[C] indicate a "field effect" in the seemingly normal surrounding white matter.
Insights
White matter lesions (WML) in aging brains involve complex molecular changes beyond ischemia, impacting immune regulation and cell processes. Surrounding white matter also shows altered gene expression, suggesting a field effect.
Area of Science:
- Neuroscience
- Molecular Biology
- Pathology
Background:
- White matter lesions (WML) are associated with cognitive decline and depression in aging brains.
- Ischemia is a known contributor to WML pathogenesis, but other mechanisms are likely involved.
Purpose of the Study:
- To investigate additional pathogenetic mechanisms of WML using an unbiased RNA microarray analysis.
- To identify altered gene expression pathways in WML compared to normal white matter.
Main Methods:
- WML were identified via MRI and pathology in donated brains.
- RNA microarray analysis compared WML with nonlesional white matter (WM[L] and WM[C]).
- Functional pathways were validated using quantitative real-time PCR and immunocytochemistry.
Main Results:
- 502 genes showed differential expression in WML compared to WM[C], involving 8 major pathways (e.g., immune regulation, apoptosis, metabolism).
- 409 genes were altered in WM[L], implicating similar pathways.
- Validation confirmed expected changes in RNA and protein expression for selected genes.
Conclusions:
- WML exhibit a complex molecular phenotype potentially involving factors beyond ischemia, such as blood-brain barrier dysfunction.
- Altered gene expression in WM[L] suggests a "field effect" in the white matter surrounding lesions.
