TY - JOUR
T1 - Transcriptomic profiling of Parkinson's disease brains reveals disease stage specific gene expression changes
AU - Cappelletti, Chiara
AU - Henriksen, Sandra Pilar
AU - Geut, Hanneke
AU - Rozemuller, Annemieke J. M.
AU - van de Berg, Wilma D. J.
AU - Pihlstrøm, Lasse
AU - Toft, Mathias
N1 - Funding Information: The study was funded by the South-Eastern Regional Health Authority, Norway and the Research Council of Norway (grant 250597, M.T.). C.C. was funded by an internal grant from Oslo Metropolitan University. L.P. also received additional funding from the Norwegian Health Association (grant 4799, L.P.) and has received a Career fellowship from the South-Eastern Regional Health Authority, Norway. W.D.J.v.d.B. received funding from the Helse Sør-Øst RHF, Norges Forskningsråd, Nasjonalforeningen for Folkehelsen, Parkinson Vereniging, Health ~Holland, Dutch Parkinson association, Health Holland, and Rotary Club Aalsmeer-Uithoorn. The authors are grateful to the Netherlands Brain Bank and its funders for providing the samples that made the study possible. Funding Information: The study was funded by the South-Eastern Regional Health Authority, Norway and the Research Council of Norway (grant 250597, M.T.). C.C. was funded by an internal grant from Oslo Metropolitan University. L.P. also received additional funding from the Norwegian Health Association (grant 4799, L.P.) and has received a Career fellowship from the South-Eastern Regional Health Authority, Norway. W.D.J.v.d.B. received funding from the Helse Sør-Øst RHF, Norges Forskningsråd, Nasjonalforeningen for Folkehelsen, Parkinson Vereniging, Health ~Holland, Dutch Parkinson association, Health Holland, and Rotary Club Aalsmeer-Uithoorn. The authors are grateful to the Netherlands Brain Bank and its funders for providing the samples that made the study possible. Publisher Copyright: © 2023, The Author(s).
PY - 2023/8
Y1 - 2023/8
N2 - 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.
AB - 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.
KW - Braak Lewy body stage
KW - Gene expression
KW - Human frontal cortex
KW - Neurodegeneration
KW - Parkinson's disease
KW - RNA-sequencing
UR - http://www.scopus.com/inward/record.url?scp=85162964492&partnerID=8YFLogxK
U2 - https://doi.org/10.1007/s00401-023-02597-7
DO - https://doi.org/10.1007/s00401-023-02597-7
M3 - Article
C2 - 37347276
SN - 0001-6322
VL - 146
SP - 227
EP - 244
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 2
ER -