9lon
From Proteopedia
Cryo-EM structure of alpha-synuclein P8 fibril
Structural highlights
FunctionSYUA_MOUSE Neuronal protein that plays several roles in synaptic activity such as regulation of synaptic vesicle trafficking and subsequent neurotransmitter release (By similarity). Participates as a monomer in synaptic vesicle exocytosis by enhancing vesicle priming, fusion and dilation of exocytotic fusion pores (By similarity). Mechanistically, acts by increasing local Ca(2+) release from microdomains which is essential for the enhancement of ATP-induced exocytosis (By similarity). Acts also as a molecular chaperone in its multimeric membrane-bound state, assisting in the folding of synaptic fusion components called SNAREs (Soluble NSF Attachment Protein REceptors) at presynaptic plasma membrane in conjunction with cysteine string protein-alpha/DNAJC5 (PubMed:20798282, PubMed:25246573). This chaperone activity is important to sustain normal SNARE-complex assembly during aging (By similarity). Also plays a role in the regulation of the dopamine neurotransmission by associating with the dopamine transporter (DAT1) and thereby modulating its activity (By similarity).[UniProtKB:P37840][1] [2] Publication Abstract from PubMedalpha-synuclein transmission and propagation are hallmarks of synucleinopathies, yet the molecular mechanisms remain elusive. Using alpha-synuclein preformed fibrils as pathological seeds, we observed a gradual decline in neuronal transmission activity during serial propagation. Fibril polymorphisms were identified from the initial generation: mini-P, with higher neuronal seeding activity, and mini-S, which accelerated recombinant alpha-synuclein aggregation. Changes in their proportions during propagation explained the overall decline in transmission activity. Cryoelectron microscopy and solid-state nuclear magnetic resonance revealed that both fibrils shared similar core regions but differed in their fuzzy coat flexibilities. The interaction between the fuzzy coat and fibril core substantially influenced neuronal transmission, a model further supported by hydrogen/deuterium exchange mass spectrometry. A mini-P-selective antibody identified active fibril types in newly propagated brain regions in human synucleinopathies. This study highlights the fuzzy coat's pivotal role in pathological protein transmission and suggests it as a potential therapeutic target for synucleinopathies. Fibril fuzzy coat is important for alpha-synuclein pathological transmission activity.,Han Y, Li J, Xia W, Li Q, Sun Z, Zeng W, Hu Y, Luk KC, Liu C, Xiang S, He Z Neuron. 2025 Apr 8:S0896-6273(25)00219-3. doi: 10.1016/j.neuron.2025.03.019. PMID:40215967[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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