TY - JOUR
T1 - α-Synuclein Conformational Plasticity
T2 - Physiologic States, Pathologic Strains, and Biotechnological Applications
AU - Li, Amanda
AU - Rastegar, Cyrus
AU - Mao, Xiaobo
N1 - Publisher Copyright:
© 2022 by the authors.
PY - 2022/7
Y1 - 2022/7
N2 - α-Synuclein (αS) is remarkable for both its extensive conformational plasticity and pathologic prion-like properties. Physiologically, αS may populate disordered monomeric, helically folded tetrameric, or membrane-bound oligomeric states. Pathologically, αS may assemble into toxic oligomers and subsequently fibrils, the prion-like transmission of which is implicated in a class of neurodegenerative disorders collectively termed α-synucleinopathies. Notably, αS does not adopt a single “amyloid fold”, but rather exists as structurally distinct amyloid-like conformations referred to as “strains”. The inoculation of animal models with different strains induces distinct pathologies, and emerging evidence suggests that the propagation of disease-specific strains underlies the differential pathologies observed in patients with different α-synucleinopathies. The characterization of αS strains has provided insight into the structural basis for the overlapping, yet distinct, symptoms of Parkinson’s disease, multiple system atrophy, and dementia with Lewy bodies. In this review, we first explore the physiological and pathological differences between conformational states of αS. We then discuss recent studies on the influence of micro-environmental factors on αS species formation, propagation, and the resultant pathological characteristics. Lastly, we review how an understanding of αS conformational properties has been translated to emerging strain amplification technologies, which have provided further insight into the role of specific strains in distinct α-synucleinopathies, and show promise for the early diagnosis of disease.
AB - α-Synuclein (αS) is remarkable for both its extensive conformational plasticity and pathologic prion-like properties. Physiologically, αS may populate disordered monomeric, helically folded tetrameric, or membrane-bound oligomeric states. Pathologically, αS may assemble into toxic oligomers and subsequently fibrils, the prion-like transmission of which is implicated in a class of neurodegenerative disorders collectively termed α-synucleinopathies. Notably, αS does not adopt a single “amyloid fold”, but rather exists as structurally distinct amyloid-like conformations referred to as “strains”. The inoculation of animal models with different strains induces distinct pathologies, and emerging evidence suggests that the propagation of disease-specific strains underlies the differential pathologies observed in patients with different α-synucleinopathies. The characterization of αS strains has provided insight into the structural basis for the overlapping, yet distinct, symptoms of Parkinson’s disease, multiple system atrophy, and dementia with Lewy bodies. In this review, we first explore the physiological and pathological differences between conformational states of αS. We then discuss recent studies on the influence of micro-environmental factors on αS species formation, propagation, and the resultant pathological characteristics. Lastly, we review how an understanding of αS conformational properties has been translated to emerging strain amplification technologies, which have provided further insight into the role of specific strains in distinct α-synucleinopathies, and show promise for the early diagnosis of disease.
KW - PMCA
KW - RT-QuIC
KW - prion-like
KW - strains
KW - tetramer
KW - α-synuclein
KW - α-synucleinopathy
UR - http://www.scopus.com/inward/record.url?scp=85135102714&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85135102714&partnerID=8YFLogxK
U2 - 10.3390/biom12070994
DO - 10.3390/biom12070994
M3 - Review article
C2 - 35883550
AN - SCOPUS:85135102714
SN - 2218-273X
VL - 12
JO - Biomolecules
JF - Biomolecules
IS - 7
M1 - 994
ER -