Criterion for Assessing Accumulated Neurotoxicity of Alpha‐Synuclein Oligomers in Parkinson's Disease

The paper introduces a parameter called "accumulated neurotoxicity" of α-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 α-syn oligomers into fibrils minimizes neurotoxicity, indicating that the formation of Lewy bodies might play a neuroprotective role. Strategies such as reducing α-syn monomer production or enhancing degradation can decrease accumulated neurotoxicity. In contrast, slower degradation (reflected by longer half-lives of monomers and free aggregates) increases neurotoxicity, supporting the idea that impaired protein degradation may contribute to Parkinson's disease progression. Accumulated neurotoxicity is highly sensitive to the half-deposition time of free α-syn aggregates into fibrils, exhibiting a sharp increase as it transitions from negligible to elevated levels, indicative of neural damage.