Elsevier

The Lancet Neurology

Volume 3, Issue 8, August 2004, Pages 496-503
The Lancet Neurology

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Lewy-body formation is an aggresome-related process: a hypothesis

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Summary

Parkinson's disease (PD) is an age-related neurodegenerative disorder that is associated with the formation of intracytoplasmic protein aggregates (Lewy-body inclusions) in neurons of the substantia nigra pars compacta and other brain areas. These inclusions were discovered over 90 years ago, but the mechanism underlying their formation and their relevance to the neurodegenerative process are unknown. Recent studies have begun to shed light on the biogenesis of Lewy bodies and suggest that they are related to aggresomes. Aggresomes are cytoprotective proteinaceous inclusions formed at the centrosome that segregate and facilitate the degradation of excess amounts of unwanted and possibly cytotoxic proteins. The concept of Lewy bodies as aggresome-related inclusions fits well with ongoing discoveries suggesting that altered protein handling might contribute to the neurodegenerative process in familial and sporadic forms of PD.

Section snippets

Organisation

Lewy bodies are spherical, 8–30 μm in diameter, intracytoplasmic inclusions that stain pink with conventional haematoxylin and eosin staining. Lewy bodies in SNc neurons typically have an intensely stained central core and a lightly stained peripheral halo (figure 1), whereas Lewy bodies in cortical neurons have a more homogenous appearance without a distinct core and halo. Electron-microscope examination of Lewy bodies reveals that the centre contains dense granular material whereas the outer

Centrosomes and aggresomes

The centrosome is a perinuclear microtubule-organising centre. Centrosomes can be distinguished from other intracellular structures because they are the main, if not the only, site of γ-tubulin and pericentrin expression (figure 2).39, 40 Centrosomes also contain at least 1% of the total intracellular proteasome content.41, 42 The primary function of the centrosome in mitotic cells is the assembly and organisation of microtubules during cell division.39, 40 Recent studies suggest that

Pathological evidence

There is growing evidence that Lewy bodies are related to aggresomes. The centrosome and aggresome proteins γ tubulin and pericentrin are present and have an aggresome-like distribution in Lewy bodies in PD and DLB. In addition, within Lewy bodies these centrosome-related proteins localise together with ubiquitinated proteins and α synuclein (figure 3).16 Many of the components of the ubiquitin-proteasome system that are recruited to the aggresome to facilitate proteolysis are also found in

A hypothesis for Lewy-body formation

The similarity between aggresomes and Lewy bodies with respect to structural organisation, protein content, and intracellular localisation suggests that these inclusions are related and could be formed in similar ways. We propose the following mechanism to account for Lewy-body formation (figure 5). Under normal circumstances, there is a dynamic equilibrium between the production and degradation of intracellular proteins (figure 5). However, this stability can be interrupted by various

Pale bodies

The presence of pale bodies is consistent with our hypothesis that Lewy bodies are a form of aggresome. Pale bodies are intracytoplasmic inclusions that have relatively low haematoxylin and eosin staining intensity, and have low and diffuse immunoreactivity for α synuclein when compared with Lewy bodies.65 We suggest that pale bodies are precursors of Lewy bodies that represent an intermediate step in the aggresomal process of Lewy body formation.

Fate of Lewy bodies

The fate of Lewy bodies may vary. Although some Lewy bodies are seen in surviving neurons, some are found free in the extracellular space, which is consistent with their preservation after destruction of the host neuron.87 In other cases, Lewy bodies may have been internalised and destroyed by the autophagic system as has been reported for aggresomes,18, 88 or engulfed along with the host neuron by activated microglia, which are observed at pathological sites in PD.89

Conclusion

Cells have an elaborate system to control increasing amounts of unwanted proteins during proteolytic stress. The centrosome or aggresome inclusion seems to be an important defence mechanism that enhances proteasomal degradation to combat the accumulation of poorly degraded proteins. Proteasomal degradation is promoted to combat the build up of poorly degraded proteins. Increasing evidence suggests that Lewy bodies in PD are a form of expanded aggresome that has developed in response to

Search strategy and selection criteria

Data for this review were identified by searches of PubMed using the search terms “aggresome”, “Lewy body”, “α synuclein”, “Parkinson's disease”, “neurodegenerative disorders”. References cited within these articles were also obtained and examined. Further references were identified from articles that the authors collected during their studies over several years. Articles published in English, Spanish, and French were reviewed. For articles published in other languages, we were able to

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