Cytoskeletal pathology of the Lewy bodies

Summary

Lewy bodies (LB), a major anatomical hallmark of Parkinson’s disease (PD), represent abnormal intracytoplasmic neuronal inclusions that show typical antigenic profiles for both the classical and cortical type. Classical or subcortical LB show a strong reaction of the periphery with monoclonal antibodies (mABs) to phosphorylated epitopes of neurofilament proteins (NFP), to micro tubule-associated proteins MAP 2 and MAP 1 (only on cryostate sections), to a mAB to paired helical filaments (PHF) which recognizes ubiquitin, and to polyclonal ABs to ubiquitin, while the core strongly reacts with a mAB to PHF (3.39) that also recognizes determinants of ubiquitin. Cortical LB show diffuse reaction with ABs to NFP and PHF, although no PHF or 15 nm filaments are found in these inclusions. Ultra-structurally, most of the filaments in LB appear to be related to NFP, part of which are uncovered by phosphatase pretreatment indicating that abnormal phosphorylation of NFP plays a role in their pathogenesis. The frequent coexistence of both LB and neurofibrillary tangles (NFT) in the same brain and even in the same neuronal perikaryon, and the sharing of several epitopes have suggested some common pathogenic relations. While both LB and NFT have been shown to contain ubiquitin, a polypeptide required for the ATP-dependent non-lysosomal protein breakdown, LB do not react with tau-protein, the major component of PHF. These data indiciate that ubiquinated proteins in LB and NFT are different: phosphorylated NFP appear to be the major component of LB, while abnormal phosphorylation of tau is suggested to be the first step in the process of NFT formation, and ubiquination may reflect a fruitless attempt of proteolytic degradation. Biochemical changes of cytoskeletal elements may be reflected by the ultrastructural changes in these neuronal inclusions, and reflect the molecular correlate of the different appearance of classical and cortical types of LB, the pathogenesis of which remains to be elucidated.