Molecular Biology of Dementia with Lewy Bodies

Abstract

The discovery of mutation of the α-synuclein gene, SNCA, in familial forms of Parkinson’s disease (PD) and subsequent identification of α-synuclein in the filamentous component of Lewy bodies indicated that fibrillization or conformational change of α-synuclein plays a central role in the pathogenesis of PD and dementia with Lewy bodies (DLB). Indeed, distribution and spreading of α-synuclein pathologies strongly correlate with disease manifestation and progression. Recent in vitro and in vivo experimental models clearly demonstrate that amyloid-like α-synuclein fibrils show prion-like properties and are able to convert normal α-synuclein to an abnormal form. For example, synthetic fibrils made of recombinant α-synuclein and sarkosyl-insoluble α-synuclein fibrils prepared from DLB brains both induce abnormal α-synuclein pathology in wild-type mice after direct inoculation into the brain. This prion-like propagation of α-synuclein through neuronal networks is the key mechanism of formation of α-synuclein pathology, and such spreading in the central and peripheral nervous systems may explain the disease progression. Thus, a detailed understanding of the molecular mechanisms of cell-to-cell propagation and its regulation is likely to be helpful for the development of disease-modifying therapy for DLB and PD.