Alpha-Synuclein Aggregation Cascade

Alpha-synuclein misfolding and aggregation into Lewy bodies is the pathological hallmark of Parkinson's disease and related synucleinopathies. A prion-like spread mechanism is now established.

Overview

Alpha-synuclein is a 140-amino acid protein abundant at presynaptic terminals, involved in vesicle trafficking and neurotransmitter release. Under pathological conditions, α-synuclein misfolds from its native unstructured state into β-sheet-rich oligomers and fibrils. These aggregate into Lewy bodies and Lewy neurites. Crucially, pathological α-synuclein spreads cell-to-cell in a prion-like manner, following predictable anatomical patterns (Braak staging).

Key Steps

  1. Native α-synuclein (unstructured monomer) exists in equilibrium with membrane-bound α-helical tetramer
  2. Stress factors (oxidation, phosphorylation, SNCA mutations/duplications) shift equilibrium toward misfolding
  3. Oligomeric intermediates form — these are the most neurotoxic species
  4. Oligomers seed fibrillization, forming amyloid-like β-sheet fibrils
  5. Fibrils accumulate in Lewy bodies; cell-to-cell transmission via exosomes, tunneling nanotubes, or direct secretion
  6. Receiving neurons take up seeds, templating misfolding of endogenous α-synuclein (prion-like propagation)

Disease Relevance

Therapeutic Targets