Is Lewy pathology in the human nervous system chiefly an indicator of neuronal protection or of toxicity?

Misfolded α-synuclein accumulates in histological inclusions constituting "Lewy pathology" found in idiopathic Parkinson disease, Parkinson disease dementia and dementia with Lewy body. The mechanism inducing α-synuclein misfolding is still unknown. The misfolded molecules form oligomers that organize into fibrils. α-Synuclein fibrils, in vitro, are capable of initiating an auto-replicating process, transforming normal molecules into misfolded molecules that aggregate. Fibrils can cross the neuronal membrane and recruit α-synuclein molecules in connected neurons. Such properties of seeding and propagation, shared with prion proteins, belong to "tissular propagons". Lewy bodies isolate harmful species from the cytoplasm and have been thought to be protective. In PRKN gene mutations, however, the absence of Lewy bodies is not associated with a more aggressive course. In idiopathic Parkinson disease, the proportion of neurons with Lewy bodies in the substantia nigra remains stable despite the progression of neuronal loss. This stable proportion suggests that Lewy bodies are eliminated at the rate at which neurons are lost because Lewy bodies cause, or invariably accompany, neuronal loss. Experimentally, cellular death selectively occurs in inclusion-bearing neurons. This set of data indicates that α-synuclein misfolding is the essential mechanism causing the lesions of Parkinson disease and dementia with Lewy body. Lewy pathology is a direct and visible evidence of α-synuclein misfolding and, as such, is an accurate marker for assessing the presence of α-synuclein misfolding even if the inclusions themselves may not be as directly causative as the molecules they accumulate.