engleski

Transcriptome analysis in neurodegenerative diseases

Rapid developments int he field of genomics, enabled by the Human Genome and HapMap projects, has opened numerous possibilities in discovery of biological mechanisms involved in functional homeostasis of biological systems. New genomic technologies have enabled for the first time investigation of thousands of genes at once, which has led to new insights into complex mechanisms of transcriptional regulation. Several studies have demonstrated robust and significant changes in transcriptional profiles of peripheral tissues in neurodegenerative diseases, such as Huntington’s disease (HD), multiple sclerosis (MS) or Alzheimer’s disease (AD). Since mutant huntingtin and alpha-synuclein are expressed in all tissues, including peripheral blood and CSF, we hypothesized that gene expression patterns in blood and CSF could in part reflect pathological processes observed in the brain. Such surrogate markers of disease activity are needed to prioritize lead compounds in animal and human drug trials. Based on this reasoning, we isolated RNA from peripheral blood of HD patients at various stages of disease progression and performed microarray analysis. Using two different microarray platforms, Affymetrix and Amersham, we identified several hundred significantly altered mRNAs that clearly distinguished HD from controls. A subset of these mRNAs was validated by QRT–PCR and correlated with disease progression and transcriptional changes in HD brain. Using a similar approach, we also isolated RNA from peripheral blood of MS patients and performed microarray analysis using Affymetrix Human Genome U133 2.0 PLUS genechips. Results of the study exhibited significant alterations in expression of genes pertaining to immune response and interleukin regulation pathways. Finally, in an additional study, we performed transcriptional profiling experiments on CSF samples from patients with AD using the Affymetrix human whole-genomes microarrays. Expression profiling experiments revealed transcriptional changes involving insulin insensitivity, interleukin 6 and beta-amyloid processing pathways. In conclusion, gene arrays may be used to identify disease markers in peripheral blood and CSF. The observed alterations may reflect pathological mechanisms involved in neurodegenerative diseases.

transcriptome; genomcis; neurodegenerative diseases

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