Lewy body disorders are a heterogenous group of neurodegenerative diseases, the morphological hallmark of which are Lewy bodies, neuronal intracytoplasmic aggregations containing misfolded fibrillar α–synuclein (AS) and a variety of other chemical substances. Lewy bodies, regardless of their location (cortical or subcortical) and the phenotype of proteinopathies (amyloidopathy, synucleinopathy, tauopathy) in which they occur, have a rather uniform biochemical and immunohistochemical profile, but may show some molecular biological and developmental diversities. Current knowledge about the molecular basis of their principal constituent, AS, a small presynaptic, natively unfolded protein that undergoes multiple conformational and translational modifications during Lewy body formation as well as the major biochemical components of these inclusions are reviewed. However, the ultimate causes and molecular pathways of their formation and the relevant role of AS with regard to neurotoxicity and neuroprotection and its final role in dysfunction and death of involved neurons are to be clarified. Although Lewy bodies and AS–positive dystrophic (Lewy) neurites are present in a large number of human diseases as well as in the aged brain, the major disorders hallmarked by these AS–positive inclusions are sporadic Parkinson disease (brainstem type of Lewy body disease) with and without dementia and different subtypes (phenotypes) of dementia with Lewy bodies. The essential clinical, neuropathological, and biochemical data of these disorders and their nosological relations are critically reviewed. Their pathological diagnosis is established by validated consensus criteria based on semiquantitative assessment of cortical and subcortical Lewy bodies as their common hallmarks, and they are accompanied by multisystem degeneration with neuronal loss, gliosis, and complex biochemical deficiencies with and without Alzheimer pathologies, the clinical impact of which is still under discussion. Considerable overlap between both these two most frequent forms of α–synucleinopathies and co–occurrence of AS, amyloid β–peptide, and tau deposits in various neurodegenerative and aging disorders suggest collision of several proteinopathies with cross–seeding and synergistic interactions, confirmed by experimental and in vitro studies. Finally, the relations between the different proteinopathies with respect to their pathogenesis are discussed, but their pathobiological relations are still to be elucidated. Despite a wealth of experimental data, there is still no consensus on whether oligomers, protofibrils, or mature fibrils (or some combination of these) of various proteins are the important toxic species that mediate neurodegeneration, nor do we understand the mechanisms by which they compromise the function and viability of selective vulnerable cells. [ABSTRACT FROM AUTHOR]