Alpha-synuclein structure and Parkinson’s disease – lessons and emerging principles

Abstract

Alpha-synuclein (αS) is the major constituent of Lewy bodies and a pathogenic hallmark of all synucleinopathathies, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). All diseases are determined by αS aggregate deposition but can be separated into distinct pathological phenotypes and diagnostic criteria. Here we attempt to reinterpret the literature, particularly in terms of how αS structure may relate to pathology. We do so in the context of a rapidly evolving field, taking into account newly revealed structural information on both native and pathogenic forms of the αS protein, including recent solid state NMR and cryoEM fibril structures. We discuss how these new findings impact on current understanding of αS and PD, and where this information may direct the field.

Carboxy‐terminal truncations of mouse α‐synuclein alter aggregation and prion‐like seeding

“…Recent structural studies suggest that C‐terminal truncation could modulate the structure of αsyn fibrils such that a species barrier‐like phenomenon could develop in which seeding of FL mouse αsyn by C‐truncated forms of αsyn would be impaired . To assess this hypothesis using the previous HEK293T cell experimental paradigm, mPFFs comprised of C‐terminally truncated αsyn were treated to cells expressing FL mouse αsyn.…”

“…These studies show that αsyn fibrils are C‐truncated upon entry to neurons and other cells; thus, the predominant pathologic αsyn species in early neuronal seeding events are heavily C‐truncated. Recent structural studies suggest that C‐terminal truncation changes the structure of αsyn fibrils , and likewise, experiments utilizing various models have demonstrated functional consequences for seeding with different C‐truncated forms of human αsyn .…”

“…Carboxy‐truncation (C‐truncation) of αsyn is one modification that has been shown in vitro and in cultured cells to increase the propensity of monomeric αsyn to spontaneously aggregate and also to modulate the prion‐like seeding activity of the fibrils . Recent characterization of αsyn fibrils through the use of cryo‐electron microscopy and other techniques suggests that C‐terminal truncation modifications can greatly alter αsyn fibril structure ; consequent alterations in prion‐like seeding as a result of these modifications may be important in explaining strain‐like diversity in fibril structure and seeding capacity isolated from LBs . Additionally, recent works have suggested that PFFs when introduced to healthy neurons are quickly trafficked for lysosomal processing where extensive truncation of exposed C‐terminal regions on the PFFs can readily occur ; this indicates that initial seeding events in a neuron likely involve truncated αsyn fibrils.…”

Effect of Parkin on methamphetamine‐induced α‐synuclein degradation dysfunction in vitro and in vivo

“…Alpha‐synuclein (α‐syn), composed of 140 amino acids, is expressed in the presynaptic and perinuclear regions of the central nervous system (Meade, Fairlie, & Mason, ). Studies have shown that under normal physiological conditions, α‐syn is low‐expression, soluble protein associated with dopamine uptake, synaptic plasticity, and vesicle maintenance (Sulzer & Edwards, ).…”

Disentangling aggregation‐prone proteins: a new method for isolating α‐synuclein species

“…Yet, in order to investigate key mechanistic or functional processes, successful isolation of different α‐Syn species is imperative. As with some other amyloid‐forming proteins, α‐Syn possesses a unique structural polydispersity whereupon the unstructured monomer can adopt a helical conformation when interacting with membranes, or β‐sheet structure when forming fibrils (Meade, Fairlie, & Mason, ).…”