A novel mutation (E83Q) unlocks the pathogenicity of human alpha-synuclein fibrils and recapitulates its pathological diversity
Kumar, S. T.; Mahul-Mellier, A.-L.; Hegde, R. N.; Moons, R.; Magalhaes, P.; Ibanez de Opakua, A.; Riviere, G.; Rostami, I.; Donzelli, S.; Zweckstetter, M.; Sobott, F.; Lashuel, H. A.
Show abstract
A novel mutation (E83Q), the first in the NAC domain of alpha-synuclein (aSyn), was recently identified in a patient with dementia with Lewy bodies. We investigated the effects of this mutation on the aggregation of aSyn monomers and the structure, morphology, dynamic, and seeding activity of the aSyn fibrils in neurons. We found that it dramatically accelerates aSyn fibrillization and results in the formation of fibrils with distinct structural and dynamic properties. In cells, this mutation is associated with higher levels of aSyn, accumulation of pS129, and increased toxicity. In a neuronal seeding model of Lewy bodies (LB) formation, the E83Q mutation significantly enhances the internalization of fibrils into neurons, induce higher seeding activity and results in the formation of diverse aSyn pathologies, including the formation of LB-like inclusions that recapitulate the immunohistochemical and morphological features of brainstem LBs observed in PD patient brains. TeaserA novel mutation (E83Q) exacerbates alpha-synuclein aggregation and toxicity and reproduces PD pathological diversity.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- The extracellular chaperone Clusterin enhances Tau aggregate seeding in a cellular model 96%
- Expression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia 95%
- Nuclear and cytoplasmic huntingtin inclusions exhibit distinct biochemical composition, interactome and ultrastructural properties 95%
Similar papers in this journal
- C9orf72-derived arginine-containing dipeptide repeats associate with axonal transport machinery and impede microtubule-based motility 96%
- Emergence of stealth polymorphs that escape α-synuclein amyloid monitoring, take over and acutely spread in neurons 95%
- VMAT2 dysfunction impairs vesicular dopamine uptake, driving its oxidation and α-synuclein pathology in DJ-1-linked Parkinson's disease neurons 95%
Similar papers in this journal
- Precision Proteoform Design for 4R Tau Isoform Selective Templated Aggregation 96%
- Parkinson's disease-related phosphorylation at Tyr39 rearranges α-synuclein amyloid fibril structure revealed by cryo-EM 95%
- A Myosin-7B dependent endocytosis pathway mediates cellular entry of α-Synuclein fibrils and polycation-bearing cargos 95%
Similar papers in this journal
- Intra-mitochondrial proteostasis is directly coupled to alpha-synuclein and Amyloid β 1-42 pathology 96%
- Neurodegeneration Risk Factor, EIF2AK3 (PERK), Influences Tau Protein Aggregation 96%
- Distinct alpha-synuclein strains derived from Parkinson's disease patient tissues trigger differential inclusion pathology in a novel biosensor cell model 95%
Similar papers in this journal
- Frontotemporal dementia-like disease progression elicited by seeded aggregation and spread of FUS 95%
- β-Amyloid Induces Microglial Expression of GPC4 and APOE Leading to Increased Neuronal Tau Pathology and Toxicity 95%
- Alpha-Synuclein pathology disrupts mitochondrial function in dopaminergic and cholinergic neurons at-risk in Parkinsons disease 94%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.