Parkinson’s disease (PD) is the second most common age-related neurodegenerative disease. It is presently only accurately diagnosed at an advanced stage by a series of motor deficits, which are predated by a litany of non-motor symptoms manifesting over years or decades. Aberrant epigenetic modifications exist across a range of diseases and are non-invasively detectable in blood as potential markers of disease. We performed comparative analyses of the methylome and transcriptome in blood from PD patients and matched controls. Our aim was to characterize DNA methylation and gene expression patterns in whole blood from PD patients as a foundational step toward the future goal of identifying molecular markers that could predict, accurately diagnose, or track the progression of PD. We found that differentially expressed genes (DEGs) were involved in the processes of transcription and mitochondrial function and that PD methylation profiles were readily distinguishable from healthy controls, even in whole-blood DNA samples. Differentially methylated regions (DMRs) were functionally varied, including near transcription factor nuclear transcription factor Y subunit alpha (NFYA), receptor tyrosine kinase DDR1, RING finger ubiquitin ligase (RNF5), acetyltransferase AGPAT1, and vault RNA VTRNA2-1. Expression quantitative trait methylation sites were found at long non-coding RNA PAX8-AS1 and transcription regulator ZFP57 among others. Functional epigenetic modules were highlighted by IL18R1, PTPRC, and ITGB2. We identified patterns of altered disease-specific DNA methylation and associated gene expression in whole blood. Our combined analyses extended what we learned from the DEG or DMR results alone. These studies provide a foundation to support the characterization of larger sample cohorts, with the goal of building a thorough, accurate, and non-invasive molecular PD biomarker.

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The organic anion transporter Adenosine triphosphate Binding Cassette subfamily C member 1 (ABCC1), also known as MRP1, has been demonstrated in murine models of Alzheimer's disease (AD) to export amyloid beta (Abeta) from the endothelial cells of the blood-brain barrier to the periphery, and that pharmaceutical activation of ABCC1 can reduce amyloid plaque deposition in the brain. Here, we show that ABCC1 is not only capable of exporting Abeta from the cytoplasm of human cells, but also that it's overexpression significantly reduces Abeta production and increases the ratio of alpha- versus beta-secretase mediated cleavage of the Amyloid Precursor Protein (APP), likely via indirect modulation of alpha-, beta-, and gamma-secretase activity.

The organic anion transporter Adenosine triphosphate Binding Cassette subfamily C member 1 (ABCC1), also known as MRP1, has been demonstrated in murine models of Alzheimer's disease (AD) to export amyloid beta (Abeta) from the endothelial cells of the blood-brain barrier to the periphery, and that pharmaceutical activation of ABCC1 can reduce amyloid plaque deposition in the brain. Here, we show that ABCC1 is not only capable of exporting Abeta from the cytoplasm of human cells, but also that it's overexpression significantly reduces Abeta production and increases the ratio of alpha-versus beta-secretase mediated cleavage of the Amyloid Precursor Protein (APP), likely via indirect modulation of alpha-, beta-, and gamma-secretase activity. Background:Alzheimer's disease (AD) is the sixth leading cause of death in the United States, and no current treatment exists that can effectively prevent or slow progression of the disease. For this reason, it is imperative to identify novel drug targets that can dramatically alter the physiological cascades that lead to neuronal cell death resulting in dementia and ultimately loss of life.The deposition of aggregated amyloid beta (Abeta) in the brain is one of the major pathological hallmarks of AD, and Abeta species result from the differential cleavage of the Amyloid Precursor Protein (APP) (Selkoe and Hardy, 2016). APP is a single-pass transmembrane protein that is highly expressed in the brain and can be cleaved by a variety of secretases to produce unique peptide fragments, the two major pathways of which are known as the alpha-and beta-secretase pathways (Selkoe and Hardy, 2016). Cleavage by an alpha-secretase releases the soluble APP alpha (sAPPalpha) fragment from the membrane into the extracellular space, which has been shown to be neuroprotective and increase neurogenesis, in vitro (Ohsawa et al., 1999), as well as play a positive role in synaptic plasticity (Ring et al., 2007;Hick et al., 2015) and memory formation (Bour et al., 2004). Alpha-secretase cleavage of APP is the by far the most common cleavage of APP in the brain (Haass and Selkoe, 1993). If, instead, the APP molecule is cleaved by a betasecretase, soluble APP beta (sAPPbeta) is released into the extracellular space, and subsequent cleavage of the remaining membrane-bound fragment by the gamma-secretase complex results in the production of Abeta, the peptide that aggregates to form amyloid plaques (Baranello et al., 2015). Because alpha-secretases cleave No GRIK1 ENSG00000171189 21 -2.6364395 -4.9042159 9.38E-07 1.52E-05 Stimulation of GRIK1 with kainic acid increased Abeta and oligomeric Abeta, likely because GRIK1 signaling increases phosphorylation and activation of NF-kappa B (Ruan et al., 2019), a transcription factor. Therefore, if the downregulation of GRIK1 observed in our experiment played a role in reducing extracellular Abeta, we would expect that the lack of GRIK1 signalling through NF-kappa B alters transcription of genes capable of altering APP metabolism, rather than GRIK1 directly playing...