Accelerated alpha-synuclein fibrillation in crowded milieu

FEBS Lett. 2002 Mar 27;515(1-3):99-103. doi: 10.1016/s0014-5793(02)02446-8.

Abstract

Parkinson's disease is the second most common age-related neurodegenerative disease, resulting from loss of dopaminergic neurons in the substantia nigra. The aggregation and fibrillation of alpha-synuclein has been implicated as a causative factor in the disease, and the process of fibril formation has been intensively studied in vitro with dilute protein solutions. However, the intracellular environment of proteins is crowded with other macromolecules, whose concentration can reach 400 g/l. To address this discrepancy, the effect of molecular crowding on alpha-synuclein fibrillation has being studied. The addition of high concentrations of different polymers (proteins, polysaccharides and polyethylene glycols) dramatically accelerated alpha-synuclein fibrillation in vitro. The magnitude of the accelerating effect depended on the nature of the polymer, its length and concentration. Our results suggest that the major factor responsible for the accelerated fibrillation under crowded conditions is the excluded volume.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Chemical Phenomena
  • Chemistry, Physical
  • Dose-Response Relationship, Drug
  • Humans
  • Macromolecular Substances
  • Muramidase / chemistry
  • Muramidase / pharmacology
  • Nerve Tissue Proteins / chemistry*
  • Nerve Tissue Proteins / drug effects
  • Nerve Tissue Proteins / metabolism
  • Parkinson Disease / metabolism
  • Polyethylene Glycols / chemistry
  • Polyethylene Glycols / pharmacology
  • Polysaccharides / chemistry
  • Polysaccharides / pharmacology
  • Protein Binding / drug effects
  • Serum Albumin, Bovine / chemistry
  • Serum Albumin, Bovine / pharmacology
  • Synucleins
  • alpha-Synuclein

Substances

  • Macromolecular Substances
  • Nerve Tissue Proteins
  • Polysaccharides
  • SNCA protein, human
  • Synucleins
  • alpha-Synuclein
  • Serum Albumin, Bovine
  • Polyethylene Glycols
  • Muramidase