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Nprl3 Gene Intron That Enhances Its Transcription in Peripheral Blood

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Nprl3 Gene Intron That Enhances Its Transcription in Peripheral Blood Scuola Internazionale Superiore di Studi Avanzati PhD Course in Functional and Structural Genomics Discovery of a human VNTR allelic variant in Nprl3 gene intron that enhances its transcription in peripheral blood Thesis submitted for the degree of “Philosophiæ Doctor” Candidate Supervisor Maria Bertuzzi Prof. Stefano Gustincich Academic Year 2014-2015 Table of contents Table of contents Abstract ....................................................................................................................................1 Introduction ..............................................................................................................................3 Gene expression regulation ..................................................................................................3 Gene expression profiling ................................................................................................5 NanoCAGE ......................................................................................................................6 TSS complexity ................................................................................................................7 Expression Quantitative Trait Loci (eQTL) .....................................................................8 Repetitive elements in the mammalian genome.................................................................10 Minisatellites and human diseases .................................................................................11 Parkinson’s disease.............................................................................................................14 PD clinical aspects..........................................................................................................15 Neuropathological features of PD ..................................................................................16 PD etiology.....................................................................................................................20 PD pathogenesis .............................................................................................................21 PD diagnosis...................................................................................................................25 Blood Transcriptomics in PD.........................................................................................28 Nitrogen permease regulator-like 3 (Nprl3).......................................................................29 Nprl3 protein ..................................................................................................................32 Mammalian Target of Rapamycin (mTOR).......................................................................33 Nprl3 takes part of a protein complex that inhibits mTORC1 .......................................34 mTORC1 and human diseases .......................................................................................36 Rapamycin effects on PD...............................................................................................38 Preliminary data .................................................................................................................39 Aim of this work.................................................................................................................40 Materials and methods............................................................................................................41 Blood collection and RNA purification..............................................................................41 Nano CAGE .......................................................................................................................41 Rapid amplification of cDNA ends (RACE)......................................................................41 Identification of Minisatellite Polymorphism ....................................................................43 Luciferase reporter assay....................................................................................................44 Genome wide association study (GWAS)..........................................................................45 i RT-PCR and Real-Time TaqMan PCR ..............................................................................45 RNA and protein preparation from blood fractions ...........................................................47 Expression plasmids ...........................................................................................................48 Cell culture, transfections and immunoblotting .................................................................48 Immunofluorescence ..........................................................................................................49 Co-immunoprecipitation ....................................................................................................49 Bromodeoxyuridine (BrdU) assay......................................................................................50 Results ....................................................................................................................................51 Blood transcriptomics of PD patients with nanoCAGE.....................................................51 Variable Number Tandem Repeats at the TSS...................................................................54 Luciferase enhancer assay ..................................................................................................55 Genome wide association study (GWAS)..........................................................................57 Tag-containing transcript identification and validation .....................................................62 Identification of tag-containing transcripts ....................................................................62 TagNprl3 transcript validation .......................................................................................66 TagNprl3 expression is linked to minisatellite genotype ...............................................68 Biological function of TagNprl3 ........................................................................................71 TagNprl3 encodes for a nucleo-cytoplasmic protein .....................................................71 TagNprl3 binds Nprl2 ....................................................................................................72 TagNprl3 inhibits proliferation ......................................................................................74 TagNprl3 overexpression has no effect on mTORC1....................................................75 RBCs are the main source of TagNprl3 in blood ...........................................................76 TagNprl3 protein is upregulated in the RBCs of heterozygous individuals...................77 TagNprl3 expression in other tissues .............................................................................79 Discussion ..............................................................................................................................80 Bibliography...........................................................................................................................88 ii Abstract Abstract Parkinson's disease (PD) is a slowly progressive degenerative disorder of the central nervous system that is classically defined in terms of motor symptoms consequent to degeneration of specific subsets of mesencephalic dopaminergic (DA) cells within substantia nigra (SN) pars compacta. No pharmacological treatment is currently available to slow or arrest the neurodegenerative process. Furthermore, accurate early diagnosis suffers from the lack of reliable biomarkers. By the time motor symptoms appear, PD patients have already lost 60-70% of DA- producing cells (Dauer & Przedborski 2003) proving that sporadic PD is diagnosed many years after the onset. It is therefore reasonable to expect that potential pharmacological treatments could be more effective if patients can benefit from it in the premotor phase. Given the systemic nature of the disease, it is not surprising that many alterations of blood physiology have been described in PD patients (Kim et al., 2004; Shults and Haas, 2005; Bongioanni et al., 1996; Migliore et al., 2002; Petrozzi et al., 2002; Salman et al., 1999; Larumbe et al., 2001; Bessler et al., 1999). In this context, a blood test to predict PD would impact the ability to identify new treatments for this incurable disease. Furthermore, it could be applied to a large number of individuals since blood is commonly used in diagnostics for being easily accessible. Gene expression analysis is a powerful tool to study complex diseases such PD and it has been extensively employed to find peripheral biomarkers (Papapetropoulos et al., 2007). In the laboratory of Prof Gustincich, in collaboration with Dr Carninci at RIKEN, Yokohama, Japan, nanoCAGE technology has been previously used to find alterations in the blood transcriptome of 20 drug naïve de novo PD patients compared to 20 Healthy Controls (HC). NanoCAGE allows the identification of Transcription Start Sites (TSSs) and therefore of the associated promoters providing an unbias quantitative description of the cellular transcriptome targeting virtually any RNA molecule present in the sample. The most up-regulated nanoCAGE tag in PD patients is located in the third intron of the gene Nitrogen Permease Regulator Like Protein 3 (Nprl3). Nprl3 gene lies on the telomeric region of human
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