Physiological C-terminal truncation of α-synuclein potentiates the prion-like formation of pathological inclusions

The making of a Lewy body: the role of alpha-synuclein post-fibrillization modifications in regulating the formation and the maturation of pathological inclusions.

“…However, the role of the C-terminal truncations in regulating α-syn aggregation has been studied almost exclusively in the context of its impact on the aggregation of monomeric α-syn, with an emphasis on truncation as potentially the primary trigger of α-syn aggregation, seeding and LB formation 27,29 . This working hypothesis is based on the consistent observation that Cterminal truncations dramatically increase the propensity of monomeric α-syn to aggregate in vitro [46][47][48][49][50][51] and that fibrils derived from C-terminal truncated α-syn fragments seed the aggregation of full-length α-syn in vitro 17,50,52 and in vivo 35,45,50,52,53 . To the best of our knowledge, the present work is the first attempt to dissect the role of post-fibrillization Cterminal cleavage of α-syn in the seeding, fibril formation and the evolution and maturation of LB-like aggregates in neurons.…”

“…,45,[48][49][50][51][52] and in cellular and animal models34,36,37,39,[41][42][43]45,[50][51][52][53] of α-synucleinopathies have consistently shown that C-terminal truncations accelerate α-syn aggregation and pathology formation.Furthermore, α-syn aggregates derived from C-terminally truncated variants of α-syn retain the ability to seed the aggregation of full-length α-syn. These observations led us to the hypothesis that C-terminal cleavage is one of the primary triggers for initiating α-syn aggregation in vivo.…”

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

“…One mechanism by which αsyn may gain toxic aggregation properties is through post‐translational modifications common in disease including phosphorylation, ubiquitination, and truncation . 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. Indeed, various truncated forms of human αsyn have been recently investigated and it has been found that seeding activity can increase or decrease depending on the specific truncation . Herein, a subset of the most common C‐truncated forms of αsyn is investigated with mouse αsyn for compatibility with NTG mouse‐based models of prion‐like seeding to further characterize how C‐truncation affects induction of pathology.…”

“…Indeed, various truncated forms of human αsyn have been recently investigated and it has been found that seeding activity can increase or decrease depending on the specific truncation . Herein, a subset of the most common C‐truncated forms of αsyn is investigated with mouse αsyn for compatibility with NTG mouse‐based models of prion‐like seeding to further characterize how C‐truncation affects induction of pathology.…”