RNA-Sequencing Reveals Similarities and Differences in Gene Expression in Vulnerable Brain Tissues of Alzheimer's and Parkinson's Diseases.

BACKGROUND

Neuropathological changes of Alzheimer's disease (AD) and Parkinson's disease (PD) can coexist in the same sample, suggesting possible common degenerative mechanisms.

OBJECTIVE

The objective of this study was to use RNA-sequencing to compare gene expression in AD and PD vulnerable brain regions and search for co-expressed genes.

METHODS

Total RNA was isolated from AD/CTL frontal cortex and PD/CTL ventral midbrain. Sequencing libraries were prepared, multiplex paired-end RNA sequencing was carried out, and bioinformatics analyses of gene expression used both publicly available (tophat2/bowtie2/Cufflinks) and commercial (Qlucore Omics Explorer) algorithms.

RESULTS

Both AD (frontal cortex, = 10) and PD (ventral midbrain, = 14) samples showed extensive heterogeneity of gene expression. Hierarchical clustering of heatmaps revealed two gene populations (AD, 376 genes; PD, 351 genes) that separated AD or PD from control samples at false-discovery rates (q) of <5% and fold changes of at least 1.3 (AD) or 1.5 (PD). 10,124 genes were co-expressed in our AD and PD samples. A very small group of these genes ( = 23) showed both low variances (<150; variance = standard deviation squared) and reduced expressions (>1.5-fold under-expression) in both AD and PD. Ingenuity Pathways Analyses (IPA, Qiagen) revealed loss of NAD biosynthesis and salvage as the major canonical pathway significantly altered in both AD and PD.

CONCLUSIONS

AD and PD in vulnerable brain regions appear to arise from and result in independent molecular genetic abnormalities, but we identified several under-expressed genes with potential to treat both diseases. NAD supplementation shows particular promise.