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

Abstract

Dementia with Lewy bodies (DLB) is epitomized by the pathognomonic manifestation of α-synuclein-laden Lewy bodies within selectively vulnerable neurons in the brain. By virtue of prion-like inheritance, the α-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 α-synuclein conformers in DLB pathobiology. Despite numerous attempts, a monolithic "α-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 α-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 α-synuclein misfolding and aggregation. Where pertinent, we show how these bona fide mechanisms may mutually accentuate α-synuclein-mediated neurodegeneration in the DLB brain.

Keywords: Alzheimer’s disease; Braak hypothesis; Fibrils; Oligomers; Parkinson’s disease.

Fig. 1

This schematic highlights the regulatory roles of α-synuclein in harmonizing synaptic homeostasis at the presynaptic terminal by coordinating vesicle trafficking, vesicle refilling, and the interactions between vesicle-associated SNARE (v-SNARE), membrane-associated SNARE (t-SNARE), and neurotransmitter release. Figures were created with Biorender.com

Fig. 2

Under pathological circumstances, α-synuclein aggregation could potentially take place in affiliation with the cellular membrane or in the cytosol. a Membrane-bound monomeric α-synuclein assumes an α-helical structure, but at elevated levels, the monomer endures conformational change to generate membrane-bound β-sheet structures that self-associate to form oligomers and fibrils. b In the cytoplasm, unfolded monomers fluctuate through conformational space to form unstable dimers, which undergo reorganization to generate oligomers of varying morphologies that eventually transform into fibrils. The erratic accretion of these fibrils leads to the amassing of intracytoplasmic Lewy bodies. c During α-synuclein fibrillogenesis, oligomers and amyloid fibrils are immensely noxious, compromising microtubule dynamics, endoplasmic reticulum–Golgi trafficking, and mitochondrial function. Figures were created with Biorender.com

Fig. 3

Schematic representation of the hypothetical DLB staging construct with stereotyped incursions of α-synuclein pathology across limbic and neocortical networks that might support the occurrence of early dementia with parkinsonism. Figures were created with Biorender.com