Poster Z15 - Bioinformatics approach to mitochondrial SLC proteins in Alzheimer’s disease

Introduction: The Solute Carrier (SLC) superfamily comprises over 400 members of membrane transport proteins in humans. These proteins play diverse roles in transporting a wide range of substrates across cell membranes, including ions, amino acids, sugars, vitamins, and neurotransmitters. However, specific roles of genes encoding SLC superfamily proteins in the aged brain with Alzheimer’s disease and other dementias remain poorly understood. We hypothesize that there is an SLC superfamily protein gene significantly altered in the caudate nucleus with Alzheimer’s disease, Parkinson’s disease, and hydrocephalus in the elderly as compared to that of controls, suggestive of a diagnostic mRNA biomarker.

Materials and

Methods: Human postmortem brain specimens were obtained from several tissue repositories of the NIH Neurobiobank and the whole transcriptome RNA-Seq was conducted in two different batches. Unsupervised bioinformatics analyses involving the principal component analysis (PCA) and gene set enrichment analysis (GSEA) suggest that genes encoding ATP6 and SLC superfamily proteins might be a starting point linking mitochondrial dysfunction in demented human brains.

Results, Conclusions, and Discussions: Among 60,000 transcript readings, 465 gene identification (ID) names contain “SLC”. Of the 465 said genes, 60 SLC superfamily proteins were investigated in control (n=5), hydrocephalus (n=5), Alzheimer’s disease (n=6), and Parkinson’s disease (n=3). We found that roughly 20 % of screened SLC genes (12 of 60) demonstrated significant alterations in the caudate nucleus with Alzheimer’s disease as compared to controls. There was a significant decrease of SLC25A6 RNA activity (200 FPKM) in the caudate nucleus with Alzheimer’s disease as compared to controls (100 FPKM, P=0.017; Mann-Whitney test). Given that SLC25A6, also known as the adenine nucleotide translocase 3 (ANT3), is a member of the SLC25 family of mitochondrial carriers and its primary function is to facilitate the exchange of ATP and ADP, our data supports the hypothesis that SLC25A6 can be a novel biomarker of Alzheimer’s disease or related dementias.

Acknowledgements (Optional): This research was made possible by the West Virginia Space Grant Consortium (WVSGC) NASA Research Initiation Grant, # 80NSSC20M0055 (to JWS) and the WVSGC NASA undergraduate research fellowship (to EB). We have used the Genomics Core supported by funding from the WV-INBRE grant (NIH P20GM103434), the COBRE ACCORD grant (P20GM121299) and the West Virginia Clinical and Translational Science Institute (WV-CTSI) grant (2U54GM104942).