ArticleActa neuropathologica2021
The subcellular arrangement of alpha-synuclein proteoforms in the Parkinson's disease brain as revealed by multicolor STED microscopy.
Article in Acta neuropathologica, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 83 papers.
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83 citing papers in PubMed, 150 citations in OpenAlex.
- Lipid droplets promote aberrant liquid-liquid phase separation of alpha-synuclein impairing energy homeostasis.EMBO reports · 2026Article
- Modeling Parkinson's pathology in human iPSC dopaminergic neurons uncovers key mechanisms of Lewy body formation and heterogeneity.Science advances · 2026Article
- PARylation in Parkinson's disease: a bridge between Lewy body formation and neuronal cell death.Cell death & disease · 2026Article
- Ultrastructural diversity and subcellular organization of nigral Lewy pathology in Parkinson's disease.Nature communications · 2026Article
- Lipid membrane remodeling by myristic acid treatment reverses Parkinson's disease α-synuclein phenotypes in patient neurons.npj metabolic health and disease · 2026Article
- WDR44 drives de novo α-synuclein aggregation at the lysosomal membrane and promotes neuronal dysfunction in Parkinson's Disease.bioRxiv : the preprint server for biology · 2026Article
- Seeing the Unseen: Super-Resolution Microscopy in Protein Aggregation Research.Chemical & biomedical imaging · 2026Review
- α-Synuclein in Lewy Body Diseases: Progress, Remaining Challenges and Future Perspectives.Expert reviews in molecular medicine · 2026Review
- Glycerol 3-phosphate acyltransferase exacerbates α-synuclein-induced toxicity by increasing lipid peroxidation.Nature communications · 2026Article
- Parkinson's disease-specific α-Synuclein variants potentially drive Lewy body formation by engaging in promiscuous and non-functional interactions.Communications biology · 2026Article
- Lipid droplets promote the aberrant liquid-liquid phase separation of alpha-synuclein leading to impaired energy homeostasis.bioRxiv : the preprint server for biology · 2025Article
- Parkinson disease is a fatty acidopathy.Nature reviews. Neurology · 2025Review
- C-terminus-dependent detection of lysosomal alpha-synuclein in nigral Parkinson's disease human brain neurons.Molecular neurodegeneration · 2025Article
- Differential role of C-terminal truncations on alpha-synuclein pathology and Lewy body formation.NPJ Parkinson's disease · 2025Article
- Alpha-synuclein interacts with regulators of ATP homeostasis in mitochondria.Nature communications · 2025Article
- Parkinson's Disease: Bridging Gaps, Building Biomarkers, and Reimagining Clinical Translation.Cells · 2025Review
- Article
- Synaptic enrichment of pSer129 alpha-synuclein correlates with dopaminergic denervation in early-stage Parkinson's disease.Nature communications · 2025Article
- α-Synuclein Pathology in Synucleinopathies: Mechanisms, Biomarkers, and Therapeutic Challenges.International journal of molecular sciences · 2025Review
- Multiplex Immunofluorescent Analysis of Alpha-Synuclein in Nigral Lewy Bodies With Heat-Induced Antibody Stripping Reveals an Intricate Multilayered Structure.Neuropathology and applied neurobiology · 2025Article
23 more citing papers are in PubMed but not listed here.
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22 authors at 7 institutions in 4 countries.
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Abstract
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.
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