The subcellular arrangement of alpha-synuclein proteoforms in the Parkinson's disease brain as revealed by multicolor STED microscopy.
Aged
Biological Specimen Banks
Brain Chemistry
Cytoplasm
/ pathology
Cytoskeleton
/ metabolism
Humans
Inclusion Bodies
/ pathology
Lewy Bodies
/ metabolism
Male
Microscopy, Confocal
Middle Aged
Neurons
/ pathology
Parkinson Disease
/ metabolism
Protein Processing, Post-Translational
Subcellular Fractions
/ metabolism
alpha-Synuclein
/ genetics
Alpha-synuclein
Lewy bodies
Parkinson's disease
Post-mortem human brain
Post-translational modifications
Super-resolution microscopy
Journal
Acta neuropathologica
ISSN: 1432-0533
Titre abrégé: Acta Neuropathol
Pays: Germany
ID NLM: 0412041
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
received:
21
02
2021
accepted:
12
05
2021
revised:
11
05
2021
pubmed:
12
6
2021
medline:
22
1
2022
entrez:
11
6
2021
Statut:
ppublish
Résumé
Various post-translationally modified (PTM) proteoforms of alpha-synuclein (aSyn)-including C-terminally truncated (CTT) and Serine 129 phosphorylated (Ser129-p) aSyn-accumulate in Lewy bodies (LBs) in different regions of the Parkinson's disease (PD) brain. Insight into the distribution of these proteoforms within LBs and subcellular compartments may aid in understanding the orchestration of Lewy pathology in PD. We applied epitope-specific antibodies against CTT and Ser129-p aSyn proteoforms and different aSyn domains in immunohistochemical multiple labelings on post-mortem brain tissue from PD patients and non-neurological, aged controls, which were scanned using high-resolution 3D multicolor confocal and stimulated emission depletion (STED) microscopy. Our multiple labeling setup highlighted a consistent onion skin-type 3D architecture in mature nigral LBs in which an intricate and structured-appearing framework of Ser129-p aSyn and cytoskeletal elements encapsulates a core enriched in CTT aSyn species. By label-free CARS microscopy we found that enrichments of proteins and lipids were mainly localized to the central portion of nigral aSyn-immunopositive (aSyn+) inclusions. Outside LBs, we observed that 122CTT aSyn+ punctae localized at mitochondrial membranes in the cytoplasm of neurons in PD and control brains, suggesting a physiological role for 122CTT aSyn outside of LBs. In contrast, very limited to no Ser129-p aSyn immunoreactivity was observed in brains of non-neurological controls, while the alignment of Ser129-p aSyn in a neuronal cytoplasmic network was characteristic for brains with (incidental) LB disease. Interestingly, Ser129-p aSyn+ network profiles were not only observed in neurons containing LBs but also in neurons without LBs particularly in donors at early disease stage, pointing towards a possible subcellular pathological phenotype preceding LB formation. Together, our high-resolution and 3D multicolor microscopy observations in the post-mortem human brain provide insights into potential mechanisms underlying a regulated LB morphogenesis.
Identifiants
pubmed: 34115198
doi: 10.1007/s00401-021-02329-9
pii: 10.1007/s00401-021-02329-9
pmc: PMC8357756
doi:
Substances chimiques
SNCA protein, human
0
alpha-Synuclein
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
423-448Informations de copyright
© 2021. The Author(s).
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