Alzheimer’s and Parkinson’s brain tissues have reduced expression of genes for mtDNA OXPHOS Proteins, mitobiogenesis regulator PGC-1α protein and mtRNA stabilizing protein LRPPRC (LRP130)

Abstract

We used RNA sequencing (RNA-seq) to quantitate gene expression in total RNA extracts of vulnerable brain tissues from Alzheimer’s disease (AD, frontal cortical ribbon) and Parkinson’s disease (PD, ventral midbrain) subjects and phenotypically negative control subjects. Paired-end sequencing files were processed with HISAT2 aligner/Cufflinks quantitation against the hg38 human genome. We observed a significant decrease in gene expression of all mtDNA OXPHOS genes in AD and PD tissues. Gene expression of the master mitochondrial biogenesis regulator PGC-1α (PPARGC1A) was significantly reduced in AD; expression of genes for mitochondrial transcription factors A (TFAM) and B1/B2 (TFB1M/TFB2M) were not significantly changed in AD and PD tissues. 2-way ANOVAs showed significant reduction in AD brain Complex I subunits’ expressions and nearly significant reductions in PD brain. We found a significant reduction in both AD and PD brain samples of expression of genes for leucine-rich pentatricopeptide repeat containing (LRPPRC, a.k.a. LRP130), a known mtRNA-stabilizing protein. Our findings suggest that AD and PD brain tissues have a reduction in mitochondrial ATP production derived from a reduction of mitobiogenesis and mtRNA stability. If true, increased brain expression of PGC-1α and/or LRPPRC may improve bioenergetics of AD and PD and alter the course of neurodegeneration in both conditions. (201 words)