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Transcriptomic profiling of Parkinson's disease brains reveals disease stage specific gene expression changes.
Cappelletti, Chiara; Henriksen, Sandra Pilar; Geut, Hanneke; Rozemuller, Annemieke J M; van de Berg, Wilma D J; Pihlstrøm, Lasse; Toft, Mathias.
Afiliação
  • Cappelletti C; Department of Mechanical, Electronics and Chemical Engineering, Faculty of Technology, Art and Design, OsloMet-Oslo Metropolitan University, Oslo, Norway.
  • Henriksen SP; Department of Research, Innovation and Education, Oslo University Hospital, Oslo, Norway.
  • Geut H; Department of Neurology, Oslo University Hospital, Oslo, Norway.
  • Rozemuller AJM; Department of Neurology, Oslo University Hospital, Oslo, Norway.
  • van de Berg WDJ; Amsterdam UMC, Section Clinical Neuroanatomy and Biobanking, Department of Anatomy and Neurosciences, Amsterdam Neuroscience, Vrije Universiteit, Amsterdam, Netherlands.
  • Pihlstrøm L; Netherlands Brain Bank, Netherlands Institute of Neurosciences, Amsterdam, Netherlands.
  • Toft M; Department of Pathology, Amsterdam UMC, Amsterdam Neuroscience, Vrije Universiteit, Amsterdam, Netherlands.
Acta Neuropathol ; 146(2): 227-244, 2023 08.
Article em En | MEDLINE | ID: mdl-37347276
Parkinson´s disease (PD) is a progressive neurodegenerative disorder characterized by both motor and non-motor symptoms. Aggravation of symptoms is mirrored by accumulation of protein aggregates mainly composed by alpha-synuclein in different brain regions, called Lewy bodies (LB). Previous studies have identified several molecular mechanisms as autophagy and inflammation playing a role in PD pathogenesis. Increased insights into mechanisms involved in early disease stages and driving the progression of the LB pathology are required for the development of disease-modifying strategies. Here, we aimed to elucidate disease stage-specific transcriptomic changes in brain tissue of well-characterized PD and control donors. We collected frontal cortex samples from 84 donors and sequenced both the coding and non-coding RNAs. We categorized our samples into groups based on their degree of LB pathology aiming to recapitulate a central aspect of disease progression. Using an analytical pipeline that corrected for sex, age at death, RNA quality, cell composition and unknown sources of variation, we found major disease stage-specific transcriptomic changes. Gene expression changes were most pronounced in donors at the disease stage when microscopic LB changes first occur in the sampled brain region. Additionally, we identified disease stage-specific enrichment of brain specific pathways and immune mechanisms. On the contrary, we showed that mitochondrial mechanisms are enriched throughout the disease course. Our data-driven approach also suggests a role for several poorly characterized lncRNAs in disease development and progression of PD. Finally, by combining genetic and epigenetic information, we highlighted two genes (MAP4K4 and PHYHIP) as candidate genes for future functional studies. Together our results indicate that transcriptomic dysregulation and associated functional changes are highly disease stage-specific, which has major implications for the study of neurodegenerative disorders.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Parkinson Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Parkinson Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article