The histological hallmark of Parkinson's disease (PD) is the presence of fibrillar aggregates called Lewy bodies (LBs) LB formation has been considered to be a marker for neuronal degeneration, because neuronal loss is found in the predilection sites for LBs To date, more than 70 molecules have been identified in LBs, in which alpha-synuclein is a major constituent of LB fibrils Alpha-synuclein immunohistochemistry reveals that diffuse cytoplasmic staining develops into pale bodies via compaction, and that LBs arise from the peripheral portion of pale bodies This alpha-synuclein abnormality is found in 10% of pigmented neurons in the substantia nigra and more than 50% of those in the locus ceruleus in PD Recent studies have suggested that oligomers and protofibrils of alpha-synuclein are cytotoxic, and that LBs may represent a cytoprotective mechanism in PD

The Lewy body in Parkinson's disease: molecules implicated in the formation and degradation of alpha-synuclein aggregates.

The histopathological hallmark of Parkinson’s disease (PD) is the presence of fibrillar aggregates referred to as Lewy bodies (LBs), in which α-synuclein is a major constituent. Pale bodies, the precursors of LBs, may serve the material for that LBs continue to expand. LBs consist of a heterogeneous mixture of more than 90 molecules, including PD-linked gene products (α-synuclein, DJ-1, LRRK2, parkin, and PINK-1), mitochondria-related proteins, and molecules implicated in the ubiquitin–proteasome system, autophagy, and aggresome formation. LB formation has been considered to be a marker for neuronal degeneration because neuronal loss is found in the predilection sites for LBs. However, recent studies have indicated that nonfibrillar α-synuclein is cytotoxic and that fibrillar aggregates of α-synuclein (LBs and pale bodies) may represent a cytoprotective mechanism in PD.

The Lewy Body in Parkinson’s Disease and Related Neurodegenerative Disorders

https://minerva-access.unimelb.edu.au/bitstream/handle/11343/191300/Guiney et al 2017.pdf

Ferroptosis and cell death mechanisms in Parkinson's disease.

Proteinaceous aggregates containing alpha-synuclein represent a feature of neurodegenerative disorders such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Despite extensive research, the mechanisms underlying alpha-synuclein aggregation remain elusive. Previously, tissue transglutaminase (tTGase) was found to contribute to the generation of aggregates by cross-linking pathogenic substrate proteins in Huntington's and Alzheimer's diseases. In this article, the role of tTGase in the formation of alpha-synuclein aggregates was investigated. Purified tTGase catalyzed alpha-synuclein cross-linking, leading to the formation of high molecular weight aggregates in vitro, and overexpression of tTGase resulted in the formation of detergent-insoluble alpha-synuclein aggregates in cellular models. Immunocytochemical studies demonstrated the presence of alpha-synuclein-positive cytoplasmic inclusions in 8% of tTGase-expressing cells. The formation of these aggregates was significantly augmented by the calcium ionophore and prevented by the inhibitor cystamine. Immunohistochemical studies on postmortem brain tissue confirmed the presence of transglutaminase-catalyzed epsilon (gamma-glutamyl)lysine cross-links in the halo of Lewy bodies in Parkinson's disease and dementia with Lewy bodies, colocalizing with alpha-synuclein. These findings, taken together, suggest that tTGase activity leads to alpha-synuclein aggregation to form Lewy bodies and perhaps contributes to neurodegeneration.

https://www.pnas.org/content/pnas/100/4/2047.full.pdf

Tissue transglutaminase-induced aggregation of α-synuclein: Implications for Lewy body formation in Parkinson's disease and dementia with Lewy bodies

Extensive nuclear localization of α-synuclein in normal rat brain neurons revealed by a novel monoclonal antibody

Cell cycle aberrations by α-synuclein over-expression and cyclin B immunoreactivity in Lewy bodies

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Cell cycle aberrations by α-synuclein over-expression and cyclin B immunoreactivity in Lewy bodies