Journal Article

Integrative gene–tissue microarray-based approach for identification of human disease biomarkers: application to amyotrophic lateral sclerosis

Lili C. Kudo, Liubov Parfenova, Nancy Vi, Kimbley Lau, Justine Pomakian, Paul Valdmanis, Guy A. Rouleau, Harry V. Vinters, Martina Wiedau-Pazos and Stanislav L. Karsten

in Human Molecular Genetics

Volume 19, issue 16, pages 3233-3253
Published in print August 2010 | ISSN: 0964-6906
Published online June 2010 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddq232
Integrative gene–tissue microarray-based approach for identification of human disease biomarkers: application to amyotrophic lateral sclerosis

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Advances in genomics and proteomics permit rapid identification of disease-relevant genes and proteins. Challenges include biological differences between animal models and human diseases, high discordance between DNA and protein expression data and a lack of experimental models to study human complex diseases. To overcome some of these limitations, we developed an integrative approach using animal models, postmortem human material and a combination of high-throughput microarray methods to identify novel molecular markers of amyotrophic lateral sclerosis (ALS). We used laser capture microdissection coupled with microarrays to identify early transcriptome changes occurring in spinal cord motor neurons or surrounding glial cells. Two models of familial motor neuron disease, SOD1G93A and TAUP301L, transgenic mice were used at the presymptomatic stage. Identified gene expression changes were predominantly model-specific. However, several genes were regulated in both models. The relevance of identified genes as clinical biomarkers was tested in the peripheral blood transcriptome of presymptomatic SOD1G93A animals using custom-designed ALS microarray. To confirm the relevance of identified genes in human sporadic ALS (SALS), selected corresponding protein products were examined by high-throughput immunoassays using tissue microarrays constructed from human postmortem spinal cord tissues. Genes that were identified by these experiments and located within a linkage region associated with familial ALS/frontotemporal dementia were sequenced in several families. This large-scale gene and protein expression study pointing to distinct molecular mechanisms of TAU- and SOD1-induced motor neuron degeneration identified several new SALS-relevant proteins (CNGA3, CRB1, OTUB2, MMP14, SLK, DDX58, RSPO2) and putative blood biomarkers, including Nefh, Prph and Mgll.

Journal Article.  12921 words.  Illustrated.

Subjects: Genetics and Genomics

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