Dynamic Modeling of Alpha-Synuclein Aggregation for the Sporadic and Genetic Forms of Parkinson's Disease

Neuroscience. 2006 Oct 27;142(3):859-70. doi: 10.1016/j.neuroscience.2006.06.052. Epub 2006 Aug 22.

Abstract

Excessive accumulation of alpha synuclein (a-syn) in the brain has been implicated in several degenerative neurological disorders, most notably Parkinson's disease. The aggregation of a-syn is the major component of intraneuronal inclusions, Lewy bodies, which are neuropathological features, observed in Parkinson's disease, Lewy body dementia, and other synucleopathies. Diverse cellular events can contribute to a-syn accumulation, aggregation, and to subsequent Lewy body formation. These factors include genetic mutations of synuclein, parkin, or the deubiquitinating enzyme, ubiquitin C-terminal hydrolase (UCH-L1), leading to reduced clearance of a-syn by the ubiquitin proteasomal pathway (UPP). Furthermore, intracellular insults include environmental factors and an age-related decrement in antioxidant defense systems that increase oxidative stress and can affect either the accumulation or clearance of a-syn. We have dynamically modeled a-syn processing in normal and in several disease states; focusing upon alterations in the aggregation and clearance of a-syn as influenced by the UPP and the oxidative stress pathways. Simulation of increased oxidative stress generates a free radical profile analogous to that reported in vivo following exposure to the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Varying model parameters of oxidative stress, UPP dysfunction, or both pathways, simulate kinetics of a-syn that corresponds with the neuropathology described for the sporadic and genetic forms of Parkinson's disease. This in silico model provides a mathematical framework that enables kinetic appraisal of pathway components to better identify and validate important pharmacological targets.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Bicarbonates / metabolism
  • Disease Models, Animal
  • Humans
  • Hydrogen Peroxide / metabolism
  • MPTP Poisoning / chemically induced
  • MPTP Poisoning / metabolism
  • MPTP Poisoning / physiopathology
  • Models, Biological*
  • Mutation
  • Neural Pathways / metabolism
  • Nitric Oxide Synthase / metabolism
  • Nonlinear Dynamics*
  • Oxidative Stress / physiology
  • Parkinson Disease / etiology
  • Parkinson Disease / genetics*
  • Parkinson Disease / metabolism*
  • Reactive Oxygen Species / metabolism
  • Ubiquitin Thiolesterase / genetics
  • alpha-Synuclein / metabolism*

Substances

  • Bicarbonates
  • Reactive Oxygen Species
  • alpha-Synuclein
  • Hydrogen Peroxide
  • Nitric Oxide Synthase
  • Ubiquitin Thiolesterase