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Transcriptional Regulators Are Upregulated in the Substantia Nigra Journal of Emerging Investigators Transcriptional Regulators are Upregulated in the Substantia Nigra of Parkinson’s Disease Patients Marianne Cowherd1 and Inhan Lee2 1Community High School, Ann Arbor, MI 2miRcore, Ann Arbor, MI Summary neurological conditions is an established practice (3). Parkinson’s disease (PD) affects approximately 10 Significant gene expression dysregulation in the SN and million people worldwide with tremors, bradykinesia, in the striatum has been described, particularly decreased apathy, memory loss, and language issues. Though such expression in PD synapses. Protein degradation has symptoms are due to the loss of the substantia nigra (SN) been found to be upregulated (4). Mutations in SNCA brain region, the ultimate causes and complete pathology are unknown. To understand the global gene expression (5), LRRK2 (6), and GBA (6) have also been identified changes in SN, microarray expression data from the SN as familial markers of PD. SNCA encodes alpha- tissue of 9 controls and 16 PD patients were compared, synuclein, a protein found in presynaptic terminals that and significantly upregulated and downregulated may regulate vesicle presence and dopamine release. genes were identified. Among the upregulated genes, Eighteen SNCA mutations have been associated with a network of 33 interacting genes centered around the PD and, although the exact pathogenic mechanism is cAMP-response element binding protein (CREBBP) was not confirmed, mutated alpha-synuclein is the major found. The downstream effects of increased CREBBP- component of protein aggregates, called Lewy bodies, related transcription and the resulting protein levels that are often found in PD brains and may contribute may result in PD symptoms, making CREBBP a potential therapeutic target due to its central role in the interactive to cell death. Abnormal SNCA may also impair protein gene network affected in PD SN. degradation (7). LRRK2 encodes the dardarin protein, which has functions related to protein phosphorylation and GTPase activity. More than 100 mutations to LRRK2 Received: June 9, 2014; Accepted: September 28, have been identified as markers of late-onset familial PD, 2015; Published: November 15, 2015 but a mechanism of action is not clear. GBA encodes an enzyme that is active in lysosomes, and while the Copyright: (C) 2015 Cowherd and Lee. All JEI articles details on how it contributes to PD remain unclear, it is are distributed under the attribution non-commercial, no speculated that impaired lysosome function prevents derivative license (http://creativecommons.org/licenses/ nerve-damaging proteins from being degraded. These by-nc-nd/3.0/). This means that anyone is free to proteins then go on to damage dopaminergic neurons. share, copy and distribute an unaltered article for non- None of these genes was identified in this analysis, commercial purposes provided the original author and which is not unusual because their associations with source is credited. PD are mutation-based and this study looked only at expression. Introduction This study identifies CREBBP, an upregulated Parkinson’s disease (PD) is a progressive gene, as interacting with most other upregulated neurodegenerative disease that affects approximately genes. CREBBP encodes CREB-binding protein, which 10 million people worldwide. Symptoms involve binds to and enhances the activity of phosphorylated movement and cognition and commonly include tremors, cAMP-response element binding protein (CREB), a bradykinesia, apathy, memory loss, and language phosphorylation-dependent transcriptional regulator. issues. Depression is common among patients and CREBBP further increases transcription via CREB by caretakers. Treatments such as levodopa and deep- acting as a scaffold for other proteins to interact with brain stimulation (DBS) are effective, but the progressive CREB. CREBBP also acetylates histone proteins, deterioration of treatment responses after 5 to 10 removing the positive charge that attracts negatively- years is an unresolved limitation of these treatments charged DNA, making the DNA region more accessible (1). Abnormal levels of dopamine, a motor control and to transcription. In this analysis, CREBBP forms reward pathway neurotransmitter, beginning in the SN the center of a large web of interacting upregulated is a proximate cause of PD symptoms (2). The SN, in genes. It is present in a majority of gene ontologies the basal ganglia of the brain, is a major dopaminergic (GO) (biological processes, molecular functions, and center. cellular components) that are overrepresented among Gene expression as a marker for PD and other the upregulated and among the upregulated genes Journal of Emerging Investigators November 15, 2015 1 Table 1: Gene expression data was extracted from 25 Journal postmortem SN of tissue samples from 9 control (5 female, 4 male) and 16 PD (3 female, 13 male) cases.Emerging Investigators constituting the CREBBP-centered interaction network. Sample Name GEO Accession Disease State Sex Many of the GO terms overrepresented in upregulated Substantia nigra normal rep1 GSM184354 Control female Substantia nigra normal rep2 GSM184355 Control male genes are related to transcriptional regulation, including Substantia nigra normal rep3 GSM184356 Control female Substantia nigra normal rep4 GSM184357 Control female chromatin organization and modification, chromosome Substantia nigra normal rep5 GSM184358 Control female Substantia nigra normal rep6 GSM184359 Control female Substantia nigra normal rep7 GSM184360 Control male organization, and histone modification. An increase Substantia nigra normal rep8 GSM184361 Control male Substantia nigra normal rep9 GSM184362 Control male in transcriptional activity, specifically by the cAMP- Substantia nigra PD rep1 GSM184363 Parkinson's Disease male Substantia nigra PD rep2 GSM184364 Parkinson's Disease male CREBBP-CREB pathway, may be an important Substantia nigra PD rep3 GSM184365 Parkinson's Disease male Substantia nigra PD rep4 GSM184366 Parkinson's Disease male pathological process in PD and may be a possible Substantia nigra PD rep5 GSM184367 Parkinson's Disease male Substantia nigra PD rep6 GSM184368 Parkinson's Disease female therapeutic target. Substantia nigra PD rep7 GSM184369 Parkinson's Disease male Substantia nigra PD rep8 GSM184370 Parkinson's Disease male Substantia nigra PD rep9 GSM184371 Parkinson's Disease female Substantia nigra PD rep10 GSM184372 Parkinson's Disease male Results Substantia nigra PD rep11 GSM184373 Parkinson's Disease male Substantia nigra PD rep12 GSM184374 Parkinson's Disease female We analyzed publicly available microarray expression Substantia nigra PD rep13 GSM184375 Parkinson's Disease male Substantia nigra PD rep14 GSM184376 Parkinson's Disease male data (GSE7621) from the postmortem SN tissues of 9 Substantia nigra PD rep15 GSM184377 Parkinson's Disease male Substantia nigra PD rep16 GSM184378 Parkinson's Disease male controls and 16 Parkinson’s disease patients (8). Table 1 shows the sample information. A moderated t-test within Table 1: Gene expression data was extracted from 25 postmortem SN tissue samples from 9 control (5 female, 4 the GEO2R platform provided the top 250 significantly male) and 16 PD (3 female, 13 male) cases. differentially expressed genes (ranked by p-value) between control and Parkinson cases (top 25 microarray with leucine-rich nuclear export signals out of the nuclear probe IDs in Table 2). A moderated t-test compares two membrane. SETD2 methylates histones and may also sets of data and returns information on the significance have a function related to the phosphorylation of RNA of the differences between those data. The t-test was polymerase II. NCOR1 effects transcription inhibition used to identify which patterns of differential expression by condensing the chromatin around specific thyroid between disease and control samples were unlikely due hormone and retinoic acid receptors. ANAPC16 is part to chance alone and are therefore possibly relevant to of a complex that controls cell cycle progression through disease state. Of those, 88 genes were downregulated ubiquitination mediation. AXIN1 is a member of several in PD and 162 genes were upregulated in PD. Figure different complexes with functions including the negative 1 shows the expression profiles of 25 samples for six regulation of Wnt signaling, apoptosis induction, and upregulated genes in PD. Genes that are downregulated phosphorylation/ubiquitination regulation. in PD are less expressed in the PD samples as a group We separately analyzed gene-gene interactions when compared to the control samples as a group. among 88 downregulated and 162 upregulated genes. Upregulated genes have a higher expression in PD Viewing interactions in String showed few groups of samples than in control samples. interacting downregulated genes. String’s database CREBBP regulates transcription factor access to contains known and predicted protein-protein interactions DNA by modifying histones and by binding to CREB, identified from published articles, experimental data, which is involved in chromatin remodeling. XPO1 and co-expression based computational prediction mediates the transport of specific snRNAs and proteins methods. When a group of genes are input together in Figure 1: Expression Profiles for Six Genes Significantly Upregulated in PD. Control sample expression in blue and PD sample expression in pink. Genes shown are (A) CREBBP, (B) XPO1, (C) SETD2, (D) NCOR1, (E) ANAPC16, and (F) AXIN1. Expression
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