title: Evidence for Immune Response, Axonal Dysfunction and Reduced Endocytosis in the Substantia Nigra in Early Stage Parkinson's Disease.
abstract: Subjects with incidental Lewy body disease (iLBD) may represent the premotor stage of Parkinson's disease (PD). To elucidate molecular mechanisms underlying neuronal dysfunction and alpha-synuclein pathology in the premotor phase of PD, we investigated the transcriptome of the substantia nigra (SN) of well-characterized iLBD, PD donors and age-matched controls with Braak alpha-synuclein stage ranging from 0-6. In Braak alpha-synuclein stages 1 and 2, we observed deregulation of pathways linked to axonal degeneration, immune response and endocytosis, including axonal guidance signaling, mTOR signaling, EIF2 signaling and clathrin-mediated endocytosis in the SN. In Braak stages 3 and 4, we observed deregulation of pathways involved in protein translation and cell survival, including mTOR and EIF2 signaling. In Braak stages 5 and 6, we observed deregulation of dopaminergic signaling, axonal guidance signaling and thrombin signaling. Throughout the progression of PD pathology, we observed a deregulation of mTOR, EIF2 and regulation of eIF4 and p70S6K signaling in the SN. Our results indicate that molecular mechanisms related to axonal dysfunction, endocytosis and immune response are an early event in PD pathology, whereas mTOR and EIF2 signaling are impaired throughout disease progression. These pathways may hold the key to altering the disease progression in PD.
authors.affiliation: Department of Anatomy and Neurosciences, section Quantitative Morphology, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands; Department of Medical genomics, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.
authors.forename: Anke A
authors.initials: AA
authors.lastname: Dijkstra
authors.affiliation: Department of Anatomy and Neurosciences, section Quantitative Morphology, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.
authors.forename: Angela
authors.initials: A
authors.lastname: Ingrassia
authors.affiliation: Department of Epidemiology and Biostatistics, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.
authors.forename: Renee X
authors.initials: RX
authors.lastname: de Menezes
authors.affiliation: Center for Neurogenomics and Cognitive Research, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.
authors.forename: Ronald E
authors.initials: RE
authors.lastname: van Kesteren
authors.affiliation: Department of Pathology, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.
authors.forename: Annemieke J M
authors.initials: AJ
authors.lastname: Rozemuller
authors.affiliation: Department of Medical genomics, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands; German Center for Neurodegenerative diseases (DZNE), Tübingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Heutink
authors.affiliation: Department of Anatomy and Neurosciences, section Quantitative Morphology, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.
authors.forename: Wilma D J
authors.initials: WD
authors.lastname: van de Berg
mesh_terms: D000368:Aged; D001369:Axons / Q000502:physiology*; D016022:Case-Control Studies; D018450:Disease Progression; D004705:Endocytosis / Q000502:physiology*; D015852:Eukaryotic Initiation Factor-2 / Q000502:physiology; D005260:Female; D006801:Humans; D017403:In Situ Hybridization; D020961:Lewy Body Disease / Q000503:physiopathology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010300:Parkinson Disease / Q000276:immunology / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology; D013378:Substantia Nigra / Q000276:immunology / Q000503:physiopathology*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology
chemical_list: D015852:Eukaryotic Initiation Factor-2; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases