ArticleActa neuropathologica2022
Brain region-specific susceptibility of Lewy body pathology in synucleinopathies is governed by α-synuclein conformations.
Article in Acta neuropathologica, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 32 citations in OpenAlex.
- Imaging nanoscopic co-assemblies of α-synuclein and Tau in human samples.Nature communications · 2026Article
- Amyloid exacerbates tau and alpha-synuclein pathologies, behavioral impairments, and neuroinflammation in a mixed dementia model.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Alpha-Synuclein in Neurodegeneration: From Shared Biology to Disease-Specific Phenotypes.Cells · 2026Review
- Tubulin transforms Tau and α-synuclein condensates from pathological to physiological.Nature communications · 2026Article
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- Parkinson disease is a fatty acidopathy.Nature reviews. Neurology · 2025Review
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- Acute introduction of monomeric or multimeric α-synuclein induces distinct impacts on synaptic vesicle trafficking at lamprey giant synapses.The Journal of physiology · 2025Article
- Synapse vulnerability and resilience across the clinical spectrum of dementias.Nature reviews. Neurology · 2025Review
- Aggregation-resistant alpha-synuclein tetramers are reduced in the blood of Parkinson's patients.EMBO molecular medicine · 2024Article
- The 'α-synucleinopathy syndicate': multiple system atrophy and Parkinson's disease.Journal of neural transmission (Vienna, Austria : 1996) · 2024Review
- Characteristic fingerprint spectrum of α-synuclein mutants on terahertz time-domain spectroscopy.Biophysical journal · 2024Article
- Molecular Deformation Is a Key Factor in Screening Aggregation Inhibitor for Intrinsically Disordered Protein Tau.ACS central science · 2024Article
- Solubility of α-synuclein species in the L62 mouse model of synucleinopathy.Scientific reports · 2024Article
- Generation of G51D and 3D mice reveals decreased α-synuclein tetramer-monomer ratios promote Parkinson's disease phenotypes.NPJ Parkinson's disease · 2024Article
- Distinct tau and alpha-synuclein molecular signatures in Alzheimer's disease with and without Lewy bodies and Parkinson's disease with dementia.Acta neuropathologica · 2024Article
- Pathobiology of Cognitive Impairment in Parkinson Disease: Challenges and Outlooks.International journal of molecular sciences · 2023Review
- Cerebrospinal fluid lipoproteins inhibit α-synuclein aggregation by interacting with oligomeric species in seed amplification assays.Molecular neurodegeneration · 2023Article
- Distribution of Lewy-related pathology in the brain, spinal cord, and periphery: the population-based Vantaa 85 + study.Acta neuropathologica communications · 2022Article
- Review
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17 authors at 9 institutions in 4 countries.
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Abstract
The protein α-synuclein, a key player in Parkinson's disease (PD) and other synucleinopathies, exists in different physiological conformations: cytosolic unfolded aggregation-prone monomers and helical aggregation-resistant multimers. It has been shown that familial PD-associated missense mutations within the α-synuclein gene destabilize the conformer equilibrium of physiologic α-synuclein in favor of unfolded monomers. Here, we characterized the relative levels of unfolded and helical forms of cytosolic α-synuclein in post-mortem human brain tissue and showed that the equilibrium of α-synuclein conformations is destabilized in sporadic PD and DLB patients. This disturbed equilibrium is decreased in a brain region-specific manner in patient samples pointing toward a possible "prion-like" propagation of the underlying pathology and forms distinct disease-specific patterns in the two different synucleinopathies. We are also able to show that a destabilization of multimers mechanistically leads to increased levels of insoluble, pathological α-synuclein, while pharmacological stabilization of multimers leads to a "prion-like" aggregation resistance. Together, our findings suggest that these disease-specific patterns of α-synuclein multimer destabilization in sporadic PD and DLB are caused by both regional neuronal vulnerability and "prion-like" aggregation transmission enabled by the destabilization of local endogenous α-synuclein protein.
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