Transcriptomic profiling of Parkinson's disease brains reveals disease stage specific gene expression changes.
Braak Lewy body stage
Gene expression
Human frontal cortex
Neurodegeneration
Parkinson's disease
RNA-sequencing
Journal
Acta neuropathologica
ISSN: 1432-0533
Titre abrégé: Acta Neuropathol
Pays: Germany
ID NLM: 0412041
Informations de publication
Date de publication:
08 2023
08 2023
Historique:
received:
21
11
2022
accepted:
06
06
2023
revised:
02
05
2023
medline:
10
7
2023
pubmed:
22
6
2023
entrez:
22
6
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37347276
doi: 10.1007/s00401-023-02597-7
pii: 10.1007/s00401-023-02597-7
pmc: PMC10329075
doi:
Substances chimiques
alpha-Synuclein
0
MAP4K4 protein, human
EC 2.7.1.11
Protein Serine-Threonine Kinases
EC 2.7.11.1
Intracellular Signaling Peptides and Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
227-244Informations de copyright
© 2023. The Author(s).
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