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

Abstract

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.

Post-translational modifications of Parkinson's disease-related proteins: Phosphorylation, SUMOylation and Ubiquitination

“…α-Syn is a soluble protein highly expressed presynaptically in neurons and can be found as an αhelical structure associated with phospholipids or in an unfolded conformation in the cytosol 3,4 Misfolded α-Syn forms oligomers and fibrils that are highly toxic to cells, and is the main component of Lewy Bodies, intracellular inclusions characteristic of PD which may promote neuroprotection through sequestration of toxic α-Syn fibrils, or directly contribute to neurotoxicity 4 . Although its physiological function remains not well understood, α-syn has been strongly implicated in synaptic plasticity and neurotransmitter release 5 .…”

Brain MRI Reveals Ascending Atrophy in Parkinson's Disease Across Severity

“…Parkinson's disease, a progressive neurodegenerative disorder, is characterized by cell death within the substantia nigra and presence of misfolded α-synuclein aggregates known as Lewy Bodies throughout the brain parenchyma (1)(2)(3). Braak and colleagues first described the pathological progression of αsynuclein aggregates in PD as occurring in an organized and ascending manner, beginning in subcortical brain structures and ending in the neocortex (4).…”

Copper and copper nanoparticles toxicity and their impact on basic functions in the body

“…The aggregation of Lewy bodies from α synuclein is not fully understood and probably abnormal degradation processes of the α synuclein, misfolding, acting of other proteins and enzymes, redox processes and phosphorylation take place in the pathology (98-100). Unfortunately, it is not even clear whether the formation of Lewy bodies is a cause or consequence of the disease and even opinions that it is a process protecting cells from another molecular damage are logical (101).…”