Abstract
Lewy body diseases are characterized by the presence of Lewy bodies, alpha-synuclein(AS)-positive inclusions in the brain. Since their main component is conformationally modified AS, aggregation of the latter is thought to be a key pathogenic event in these diseases. The analysis of inclusion body constituents gives additional information about pathways also involved in the pathology of synucleinopathies. Widespread mitochondrial dysfunction is very closely related to disease development. The impairment of protein degradation pathways, including both the ubiquitin-proteasome system and the autophagy-lysosome pathway also play an important role during the development of Lewy body diseases. Finally, differential expression changes of isoforms corresponding to genes primarily involved in Lewy body formation point to alternative splicing as another important mechanism in the development of Parkinson’s disease, as well as dementia with Lewy bodies. The present paper attempts to give an overview of recent molecular findings related to the pathogenesis of Lewy body diseases.
Highlights
Lewy body diseases are characterized by the presence of Lewy bodies, alphasynuclein(AS)-positive inclusions in the brain
Phosphorylation of parkin induces its translocation to mitochondria so that PTEN-induced kinase 1 (PINK1) mutations could cause Parkinson’s disease (PD) by decreased PINK1 kinase activity that at the same time would lead to low parkin levels within mitochondria [96]
Changes in protein-protein interactions resulting from the lack or overrepresentation of some of the isoforms could be responsible for diminution or gain of function. Since both parkin and synphilin-1 are involved in the proteasome mediated protein degradation, and an important proteasome dysfunction can be observed in synucleinopathies, one of the mechanisms leading to such a dysfunction could be the alteration of alternative splicing
Summary
LBD are characterized by the presence on intraneuronal proteinaceous inclusions called Lewy bodies (LBs) with AS as their main component. Whereas these are found mainly within the brainstem in the case of PD, their widespread distribution through almost all brain areas is a characteristic feature in DLB. The presence of LB is accompanied by neurodegeneration in the affected areas, the brainstem affectation in PD causes parkinsonian symptoms and the additional cortical affectation in DLB, dementia
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