Summary

The constitutive fibrils of the Lewy body contain all three neurofilament subunits in an altered form. Our recent in situ hybridization studies of the low molecular weight subunit of the neurofilament suggest that altered neurofilament expression is not implicated in the formation of the Lewy body. Using the Mallory body of the liver as a dynamic model of intermediate filament inclusion formation, we also demonstrated that the filaments are first normally assembled and modified in a subsequent step. We propose a speculative model of Lewy body pathogenesis in which neurofilaments are assembled normally and subsequently undergo phosphorylation, proteolysis and crosslinking at a post-translational/post-assembly stage.

Introduction

The Lewy body (LB) is a major pathological feature of Lewy body disorders including idiopathic Parkinson's disease (PD) and diffuse Lewy body disease (DLB). As we discussed in our recent review (Pollanen et al., 1993), direct and indirect analysis of the LB has shown that its constitutive fibrils contain all three neurofilament (NF) subunits of molecular weights 68 kD (NF-L), 150 kD (NF-M) and 200 kD (NF-H) in both phosphorylated and nonphosphorylated forms. The NF epitopes are spatially distributed with a predominance of NF-L or amino-termini of NF subunits in the central portion of the inclusion, a phenomenon which suggests a possible segregation of proteolytic fragments. The presence of ubiquitin, ubiquitin-C-terminal hydrolase and ingestin (multicatalytic proteinase or proteasome) in the LB also suggests that proteolysis is implicated in its pathogenesis. Finally, the detergent-insolubility of these fibrils indicates that the NF proteins which form the LB are further altered and probably crosslinked. Taken together, these studies suggest that altered phosphorylation/dephosphorylation and proteolysis of NF are key post-translational events in LB pathogenesis.