Gene expression changes in postmortem tissue from the rostral pons of multiple system atrophy patients.

ABSTRACT

Multiple system atrophy (MSA) is a neurodegenerative disease characterized by various degrees of Parkinsonism, cerebellar ataxia, and autonomic dysfunction. In this report, Affymetrix DNA microarrays were used to measure changes in gene expression in the rostral pons, an area that undergoes extensive damage in MSA, but not other synucleinopathies. Significant changes in expression of 254 genes (180 downregulated and 74 upregulated) occurred in pons tissue from MSA patients when compared with control patients. The downregulated genes were primarily associated with biological functions known to be impaired in Parkinson's disease (PD) and other neurological diseases; for example, downregulation occurred in genes associated with mitochondrial function, ubiquitin-proteasome function, protein modification, glycolysis/metabolism, and ion transport. On the other hand, upregulated genes were associated with transcription/RNA modification, inflammation, immune system function, and oligodendrocyte maintenance and function. Immunocytochemistry, in conjunction with quantitative image analysis, was carried out to characterize alpha-synuclein protein expression as glial cytoplasmic inclusions in the pontocerebellar tract in rostral pons tissue and to determine the relationship between the amount of aggregated alpha-synuclein protein and changes in specific gene expression. Of the regulated genes, 86 were associated with the amount of observed aggregated alpha-synuclein protein in the rostral pons tissue. These data indicate that cells in the pons of MSA patients show changes in gene expression previously associated with the substantia nigra of PD patients and/or other neurological diseases, with additional changes, for example related to oligodendrocyte function unique to MSA.