Criterion for assessing accumulated neurotoxicity of alpha-synuclein oligomers in Parkinson's disease

Abstract

The paper introduces a parameter called "accumulated neurotoxicity" of -syn oligomers, which measures the cumulative damage these toxic species inflict on neurons over time, given the years it typically takes for such damage to manifest. A threshold value for accumulated neurotoxicity is estimated, beyond which neuron death is likely. Numerical results suggest that rapid deposition of -syn oligomers into fibrils minimizes toxicity, indicating that the formation of Lewy bodies might play a neuroprotective role. Strategies such as reducing -syn monomer production or enhancing degradation can decrease accumulated toxicity. In contrast, slower degradation (reflected by longer half-lives of monomers and free aggregates) increases toxicity, supporting the idea that impaired protein degradation may contribute to Parkinsons disease progression. The study also examines the sensitivity of accumulated toxicity to different model parameters.