Lewy Bodies: A Spectator or Salient Killer?

Lewy bodies (LBs) are characteristic hallmarks of Parkinson's disease (PD). However, their role in the pathology of PD is not established yet. Are they primary events in the neurodegenerative process or only secondary phenomena? Are they signs of protecting neurons from toxicity or are they toxic per se? How are they are formed? Are LBs targets for therapeutic strategies? Addressing these questions may be of pivotal importance to unravel the basic mechanisms of neurodegeneration in PD. On the basis of current evidence, we intend to elucidate the possible role of LBs as triggers and/or markers of disease progression in PD. We present evidence for the morphogenesis of brain stem and cortical LBs, the role in neuronal cell death mechanisms, which seem to be correlated with the adhesion of LBs to and finally disruption of their inner neuronal membrane. Taken as such, LBs would be salient killers of nerve cells. However, they may also play a neuroprotective role in the early phases of neuronal pathology (LBs as a spectator), yet harmful to neuronal stability in later stages of LB development. Generation of LB pathology in the periphery (early subclinical Braak stage) might be due to reactive oxygen species (ROS) due to (chronic) bacteria-induced and/or otherwise intestinal inflammation, both leading to alpha-synuclein structural changes, oligomerization, seeding and propagation in a prion-like mechanism. If so, LB generation is a secondary process following ROS/inflammation pathology. Therapeutic implication based on LB pathology include drug development to inhibit protein misfolding, templating and transmission or vaccination against LBs, neuron regeneration strategies, anti-inflammatory and anti-biotic drugs as well as nutritional specialities to prevent intestine intoxications. In conclusion, evidence suggests LBs to be secondary hallmarks of PD pathology, induced by ROS/inflammation or other pathological triggers able to modify protein (alpha-synuclein) steric/chemical properties. Therapeutic strategies based on LB pathologies are devoted to reduce neuron cell death mechanisms in their time course and severity.