Sandbox:Sarang 20231222 BI3323-Aug2025

From Proteopedia

== Structures of α-synuclein filaments from human brains with Lewy pathology (8A9L)==

This page describes the brain-derived α-synuclein filament structure (PDB: 8A9L), representing the characteristic **Lewy fold** observed in Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), and Dementia with Lewy Bodies (DLB). (From Yang et al., 2022).

1 Function
2 Disease
3 Relevance
4 Structural highlights

Function

α-Synuclein is a presynaptic neuronal protein involved in:

• Regulation of synaptic vesicle trafficking

• Promotion of SNARE complex assembly

• Modulation of dopamine release

• Membrane binding through amphipathic repeats

Under physiological conditions it is natively unstructured. Its central

hydrophobic region (NAC, residues 61–95) drives pathological aggregation, forming β-sheet fibrils in disease states.

Disease

Aggregated α-synuclein forms Lewy bodies and Lewy neurites, the hallmark pathological inclusions in:

• Parkinson’s disease (PD)

• Parkinson’s disease dementia (PDD)

• Dementia with Lewy bodies (DLB)

Yang et al. found that all PD/PDD/DLB patient brains examined contained

the **same single-protofilament conformation**: the Lewy fold. This supports the concept of a molecular continuum among these diseases.

Relevance

The Lewy fold structure is important because it:

• Explains how α-synuclein aggregates propagate in a prion-like manner

• Distinguishes Lewy diseases from Multiple System Atrophy (MSA), which

 has a completely different two-protofilament fold

• Identifies structural targets for diagnostics and therapeutics

 (cofactor groove, NAC region, β-sheet architecture)

• Supports development of fold-specific biomarkers

• Helps explain why PD/PDD/DLB differ in behavior from MSA

Because no disease-modifying therapy exists for PD or DLB, structural

insights from 8A9L are essential for drug design.

Structural highlights

Key features of the Lewy fold (8A9L):

• Single protofilament (vs two in MSA)

• Residues 31–100 form the structured core

• Nine β-strands (β1–β9) arranged in three layers

• Two disconnected peptide densities (Island A & Island B)

• A unique cofactor-binding groove near residues K32–K45

• Stabilizing salt bridge: E35–K80

• Right-handed twist (MSA fold = left-handed)

The structural differences explain why PD/PDD/DLB and MSA behave like distinct α-synuclein strains.

Lewy Fold vs MSA Fold

Lewy diseases (PD/PDD/DLB): • Single protofilament • E35–K80 salt bridge • Right-handed twist • Structure = Lewy fold

Multiple System Atrophy (MSA): • Two protofilaments (PF-I and PF-II) • E46–K80 salt bridge • Left-handed twist • Different β-strand topology and cofactor positions

Figures from the Paper

thumb|500px|Extended Data Figure 6. Comparison of substructures within the Lewy fold (PDB 8A9L) and recombinant α-synuclein fibrils. Panels (a–f) show which regions of the Lewy fold align closely with recombinant polymorphs and which diverge. Conserved segments such as residues 61–72 show low RMSDs, whereas other β-strand arrangements vary significantly, highlighting disease-specific conformational features.

thumb|500px|Extended Data Figure 1. Immunostaining of α-synuclein inclusions (Syn1 antibody, 1:1000) from PD, PDD, and DLB brain tissue. Brown-stained inclusions represent Lewy bodies and Lewy neurites in cingulate and frontal cortex regions. These confirm abundant aggregated α-synuclein in the regions used for cryo-EM structural determination.

thumb|500px|Extended Data Figure 5. Cryo-EM micrographs showing coexistence of twisted (blue-annotated) and untwisted (red-annotated) segments within single α-synuclein filaments. This demonstrates structural heterogeneity along human brain-derived Lewy filaments, with distinct regions contributing to twisted versus untwisted 2D class averages.

thumb|550px|Figure 3. Schematic comparison of the Lewy fold (PDB 8A9L) with MSA protofilament folds (PF-IA, PF-IB, PF-IIA, PF-IIB). Lewy filaments form a single right-handed protofilament, whereas MSA filaments contain two asymmetric protofilaments with a left-handed twist. Key distinguishing interactions, including the Lewy-specific E35–K80 salt bridge versus the MSA-specific E46–K80 interaction, are highlighted. NAC region shown in green and N-terminal region in orange.

I tried a lot but images not getting attached. Can access these images from uploaded file.