Selective vulnerability in α-synucleinopathies

Abstract

Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy are neurodegenerative disorders resulting in progressive motor/cognitive deficits among other symptoms. They are characterised by stereotypical brain cell loss accompanied by the formation of proteinaceous aggregations of the protein α-synuclein (α-syn), being, therefore, termed α-synucleinopathies. Although the presence of α-syn inclusions is a common hallmark of these disorders, the exact nature of the deposited protein is specific to each disease. Different neuroanatomical regions and cellular populations manifest a differential vulnerability to the appearance of protein deposits, cell dysfunction, and cell death, leading to phenotypic diversity. The present review describes the multiple factors that contribute to the selective vulnerability in α-synucleinopathies. We explore the intrinsic cellular properties in the affected regions, including the physiological and pathophysiological roles of endogenous α-syn, the metabolic and genetic build-up of the cells and their connectivity. These factors converge with the variability of the α-syn conformational strains and their spreading capacity to dictate the phenotypic diversity and regional vulnerability of each disease. Finally, we describe the exogenous and environmental factors that potentially contribute by igniting and modulating the differential pathology in α-synucleinopathies. In conclusion, we think that it is the confluence of this disruption of the cellular metabolic state and α-syn structural equilibrium through the anatomical connectivity which appears to initiate cascades of pathological processes triggered by genetic, environmental, or stochastic events that result in the "death by a thousand cuts" profile of α-synucleinopathies.

Fig. 1

α-Syn potential gain/loss of function mechanisms. While α-syn is able to increase ATP synthase activity in its monomeric state, it reduces its activity in its oligomeric state. Oligomers have also been reported to reduce NKA function and cause lysosomal and ER stress. Mutations in α-syn have also been shown to alter the ratio of monomers with supramolecular species and to impair synaptic function. Similar mechanisms could play a role in sporadic disease. We hypothesise the existence of regulated physiological α-syn prionoids and their dysregulation contributing to disease perhaps by both gain and loss of function mechanisms

Fig. 2

α-Syn selective vulnerability of SNc neurons/VTA neurons/oligodendrocytes. While complex arborisation, neuromelanin content, DA associated damage, high energetic burden and α-syn levels are common features of both SNc and VTA neurons, there are fundamental differences in calcium flux and buffering that may account for differential vulnerability in these cells. However, the fact remains that these properties have not been shown to be core feature of cells that degenerate in other α-synucleinopathies such as oligodendrocytes. More studies focusing on glial populations, and perhaps their calcium metabolism, are needed to determine whether this is a critical feature of α-synucleinopathies

Fig. 3

GTEX expression data. This analysis shows that the median expression of SNCA in the substantia nigra (red arrow) is lower than some other parts of the brain, e.g., cerebellar hemispheres (green arrow). Brain expression is overall high (light yellow plots), although high expression is also noted in tibial nerve (dark yellow plot) and whole blood (magenta). Vertical axis: transcripts per kilobase million (TPM)