α-Synuclein-mediated neurodegeneration in Dementia with Lewy bodies: the pathobiology of a paradox

Dementia with Lewy bodies (DLB) is epitomized by the pathognomonic manifestation of alpha-synuclein-laden Lewy bodies within selectively vulnerable neurons in the brain. By virtue of prion-like inheritance, the alpha-synuclein protein inexorably undergoes extensive conformational metamorphoses and culminate in the form of fibrillar polymorphs, instigating calamitous damage to the brain's neuropsychological networks. This epiphenomenon is nebulous, however, by lingering uncertainty over the quasi pathogenic behavior of alpha-synuclein conformers in DLB pathobiology. Despite numerous attempts, a monolithic alpha-synuclein paradigm that is able to untangle the enigma enshrouding the clinicopathological spectrum of DLB has failed to emanate. In this article, we review conceptual frameworks of alpha-synuclein dependent cell-autonomous and non-autonomous mechanisms that are likely to facilitate the transneuronal spread of degeneration through the neuraxis. In particular, we describe how the progressive demise of susceptible neurons may evolve from cellular derangements perpetrated by alpha-synuclein misfolding and aggregation. Where pertinent, we show how these bona fide mechanisms may mutually accentuate alpha-synuclein-mediated neurodegeneration in the DLB brain.

Automated summary

Dementia with Lewy bodies (DLB) is characterized by the presence of alpha-synuclein-laden Lewy bodies in the brain, leading to significant damage to the brain's neuropsychological networks. However, there is still uncertainty surrounding the pathogenic role of alpha-synuclein in DLB pathobiology.