Dynamic modeling of alpha-synuclein aggregation for the sporadic and genetic forms of Parkinson's disease.
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.
Raichur
A
A
Cellworks Group Inc., 13962 Pierce Road, Saratoga, CA, 95070, USA.
Vali
S
S
Gorin
F
F
D000818:Animals; D001639:Bicarbonates / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D020267:MPTP Poisoning / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D008954:Models, Biological; D009154:Mutation; D009434:Neural Pathways / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D017711:Nonlinear Dynamics; D018384:Oxidative Stress / Q000502:physiology; D010300:Parkinson Disease / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics; D051844:alpha-Synuclein / Q000378:metabolism*
D001639:Bicarbonates; D017382:Reactive Oxygen Species; D051844:alpha-Synuclein; D006861:Hydrogen Peroxide; D019001:Nitric Oxide Synthase; D043222:Ubiquitin Thiolesterase