9IC7

Cryo-EM structure of alpha-synuclein fibrils formed in artificial cerebrospinal fluid (aCSF)

Summary for 9IC7

• Entry DOI: 10.2210/pdb9ic7/pdb
• EMDB information: 52833
• Descriptor: Alpha-synuclein (1 entity in total)
• Functional Keywords: parkinson, csf, alpha-synuclein, neurodegeneration, protein fibril
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 14
• Total formula weight: 202665.51

Authors

Snieckute, R.,Sulskis, D.,Jocyte, A.,Venclovaite, U.,Tamulyte, R.,Ziaunys, M.,Smirnovas, V.,Sakalauskas, A. (deposition date: 2025-02-14, release date: 2025-12-03)

Primary citation

Snieckute, R.,Sulskis, D.,Jocyte, A.,Venclovaite, U.,Tamulyte, R.,Ziaunys, M.,Smirnovas, V.,Sakalauskas, A.
Formation of Condition-Dependent Alpha-Synuclein Fibril Strain in Artificial Cerebrospinal Fluid.
Adv Sci, :e05228-e05228, 2025

PubMed Abstract: α-Synuclein (aSyn) is an intrinsically disordered protein involved in neurotransmission and synaptic plasticity. The pathological aggregation of this protein is a hallmark of synucleinopathies such as Parkinson's disease (PD) or Multiple System Atrophy (MSA). Misfolded aSyn, which primarily originates in the cell cytosol, transmits between neurons, promoting a prion-like propagation. However, extracellular environments such as interstitial and cerebrospinal fluids (ISF & CSF) play a major role in its clearance and pathological transformation. The molecular components of CSF, including proteins, glycosaminoglycans, and metal ions, may influence the aggregate morphology, structure, and cytotoxicity to cells. To better understand how extracellular composition affects aggregates and their formation, artificial cerebrospinal fluid (aCSF) is employed to mimic potential aggregation processes occurring in CSF. Distinct aSyn fibrils are observed that exhibited low stability outside aCSF, and the removal of key CSF components led to its structural alterations. Cryo-electron microscopy revealed that these fibrils possess an electron density pocket coordinated with polar basic AAs (K43, K45, H50) that is also observed in aggregates obtained from PD and MSA patients. The findings illustrate the importance of physiologically relevant conditions in studying aSyn aggregation and may explain why disease-related fibril structure replication in vitro has not yet been successful.

PubMed: 41262012
DOI: 10.1002/advs.202505228

Experimental method

ELECTRON MICROSCOPY (2.9 Å)