Different structures and pathologies of α-synuclein fibrils derived from preclinical and postmortem patients of Parkinson’s disease

Abstract

Abstractα-Synuclein (α-syn) fibrillar aggregates are the major component of Lewy bodies and Lewy neurites presenting as the pathology hallmark of Parkinson’s disease (PD). Studies have shown that α-syn is potential to form different conformational fibrils associated with different synucleinopathies, but whether the conformation of α-syn fibrils changes in different phases of related diseases is to be explored. Here, we amplified α-syn aggregates from the cerebrospinal fluid (CSF) of preclinical (pre-PD) and late-stage postmortem PD (post-PD) patients. Our results show that compared to the CSF of pre-PD, that of post-PD is markedly stronger in seeding in vitro α-syn aggregation, and the amplified fibrils are more potent in inducing endogenous α-syn aggregation in neurons. Cryo-electron microscopic structures further reveal that the difference between the pre-PD- and post-PD-derived fibrils lies on a minor polymorph which in the pre-PD fibrils is morphologically straight, while in the post-PD fibrils represents a single protofilament assembled by a distinctive conformation of α-syn. Our work demonstrates structural and pathological differences between pre-PD and post-PD α-syn aggregation and suggests potential alteration of α-syn fibrils during the progression of PD clinical phases.Significance StatementIncreasing evidence support different conformational α-syn fibrils in patients with different α-synucleinopathies, but whether the conformation of α-syn fibrils changes in different phases of related diseases is unknown. Here, we show that α-syn fibrils amplified from the cerebrospinal fluid (CSF) of the late-stage postmortem PD (post-PD) patient are more potent in inducing endogenous α-syn aggregation in neurons than that amplified from the preclinical (pre-PD) patient. Cryo-EM structures further reveal that the post-PD fibrils contain a novel conformation that is distinct from either the pre-PD fibrils or those previously reported. Our work suggests conformational evolution of α-syn fibrils along with PD progression.

Structure of alpha-synuclein fibrils derived from human Lewy body dementia tissue

“…Finally, studies in vitro and in model systems can facilitate the development of candidate therapeutics capable of inhibiting fibril accumulation. Other amplification methods, utilizing tissue extracts or cerebrospinal fluid as starting material, have produced Asyn fibrils with structures that diverge from the structures determined for tissue-derived fibrils in MSA and LBD, indicating that some aspects of the amplification protocol described here, such as fragmentation and incubation conditions, are important for templating structure during amplification [58][59][60] .…”

Anionic lipid vesicles have differential effects on the aggregation of early onset-associated α-synuclein missense mutants

“…For the mutant structures, the mutation is highlighted in orange ( 56 , 57 , 58 , 59 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 ). Further structures are pending ( 90 , 91 ). αS, α-synuclein.…”