Selective vulnerability in α-synucleinopathies
File(s)
Author(s)
Alegre-Abarrategui, Javier
Brimblecombe, Katherine R
Roberts, Rosalind F
Velentza-Almpani, Elisavet
Tilley, Bension S
Type
Journal Article
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.
Date Issued
2019-11-01
Date Acceptance
2019-04-05
Citation
Acta Neuropathologica, 2019, 138 (5), pp.681-704
ISSN
1432-0533
Publisher
Springer (part of Springer Nature)
Start Page
681
End Page
704
Journal / Book Title
Acta Neuropathologica
Volume
138
Issue
5
Copyright Statement
© The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Sponsor
National Institute for Health Research
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/31006067
PII: 10.1007/s00401-019-02010-2
Grant Number
RDA26
Subjects
Science & Technology
Life Sciences & Biomedicine
Clinical Neurology
Neurosciences
Pathology
Neurosciences & Neurology
MULTIPLE SYSTEM ATROPHY
SLEEP BEHAVIOR DISORDER
ENTERIC NERVOUS-SYSTEM
PARKINSONS-DISEASE
SUBSTANTIA-NIGRA
DOPAMINERGIC-NEURONS
LEWY BODIES
COGNITIVE IMPAIRMENT
IN-VIVO
1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE MPTP
Neurology & Neurosurgery
1103 Clinical Sciences
1109 Neurosciences
Publication Status
Published
Coverage Spatial
Germany
Date Publish Online
2019-04-20