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

ABSTRACT: ?-Synuclein (?syn) aggregates into toxic fibrils in multiple neurodegenerative diseases where these fibrils form characteristic pathological inclusions such as Lewy bodies (LBs). The mechanisms initiating ?syn aggregation into fibrils are unclear, but ubiquitous post-translational modifications of ?syn present in LBs may play a role. Specific C-terminally (C)-truncated forms of ?syn are present within human pathological inclusions and form under physiological conditions likely in lysosome-associated pathways, but the roles for these C-truncated forms of ?syn in inclusion formation and disease are not well understood. Herein, we characterized the in vitro aggregation properties, amyloid fibril structures, and ability to induce full-length (FL) ?syn aggregation through prion-like mechanisms for eight of the most common physiological C-truncated forms of ?syn (1-115, 1-119, 1-122, 1-124, 1-125, 1-129, 1-133, and 1-135). In vitro, C-truncated ?syn aggregated more readily than FL ?syn and formed fibrils with unique morphologies. The presence of C-truncated ?syn potentiated aggregation of FL ?syn in vitro through co-polymerization. Specific C-truncated forms of ?syn in cells also exacerbated seeded aggregation of ?syn. Furthermore, in primary neuronal cultures, co-polymers of C-truncated and FL ?syn were potent prion-like seeds, but polymers composed solely of the C-truncated protein were not. These experiments indicated that specific physiological C-truncated forms of ?syn have distinct aggregation properties, including the ability to modulate the prion-like aggregation and seeding activity of FL ?syn. Proteolytic formation of these C-truncated species may have an important role in both the initiation of ?syn pathological inclusions and further progression of disease with strain-like properties.

SUBMITTER: Sorrentino ZA

PROVIDER: S-EPMC6295729 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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

Sorrentino Zachary A ZA Vijayaraghavan Niran N Gorion Kimberly-Marie KM Riffe Cara J CJ Strang Kevin H KH Caldwell Jason J Giasson Benoit I BI

The Journal of biological chemistry 20181016 49

α-Synuclein (αsyn) aggregates into toxic fibrils in multiple neurodegenerative diseases where these fibrils form characteristic pathological inclusions such as Lewy bodies (LBs). The mechanisms initiating αsyn aggregation into fibrils are unclear, but ubiquitous post-translational modifications of αsyn present in LBs may play a role. Specific C-terminally (C)-truncated forms of αsyn are present within human pathological inclusions and form under physiological conditions likely in lysosome-associ ...[more]

PMID: 30327435

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Project description:Leucine-rich repeat kinase 2 (LRRK2) and α-synuclein share enigmatic roles in the pathobiology of Parkinson's disease (PD). LRRK2 mutations are a common genetic cause of PD which, in addition to neurodegeneration, often present with abnormal deposits of α-synuclein in the form of Lewy-related pathology. As Lewy-related pathology is a prominent neuropathologic finding in sporadic PD, the relationship between LRRK2 and α-synuclein has garnered considerable interest. However, whether and how LRRK2 might influence the accumulation of Lewy-related pathology remains poorly understood. Through stereotactic injection of mouse α-synuclein pre-formed fibrils (PFF), we modeled the spread of Lewy-related pathology within forebrain regions where LRRK2 is most highly expressed. The impact of LRRK2 genotype on the formation of α-synuclein inclusions was evaluated at 1-month post-injection. Neither deletion of LRRK2 nor G2019S LRRK2 knockin appreciably altered the burden of α- synuclein pathology at this early timepoint. These observations fail to provide support for a robust pathophysiologic interaction between LRRK2 and α-synuclein in the forebrain in vivo . There was, however, a modest reduction in microglial activation induced by PFF delivery in the hippocampus of LRRK2 knockout mice, suggesting that LRRK2 may contribute to α-synuclein-induced neuroinflammation. Collectively, our data indicate that the pathological accumulation of α-synuclein in the mouse forebrain is largely independent of LRRK2.HighlightsAdult mice accumulate α-synuclein pathology in the hippocampus and cortex following stereotactic injection with α-synuclein PFFs, with negligible influence of LRRK2 genotype. Hippocampal and cortical α-synuclein pathology elicits the concomitant accrual of phosphorylated tau, reactive astrogliosis, and microglial activation. Absence of endogenous LRRK2 attenuates microglial activation in the dorsal hippocampus induced by PFFs, but not in the entorhinal cortex. Accumulation of α-synuclein inclusions and related neuropathologic changes were strongly associated across the hippocampal dorsal-ventral axis, regardless of LRRK2 genotype.

Project description:α-synuclein (αSyn) is the main protein component of Lewy bodies, intracellular inclusions found in the brain of Parkinson's disease (PD) patients. Neurotoxic αSyn species are broadly modified post-translationally and, in patients with genetic forms of PD, carry genetically encoded amino acid substitutions. Mutations and C-terminal truncation can increase αSyn oligomerization and fibrillization. Although several genetic mouse models based on αSyn mutations and/or truncations exist, there is still a lack of mouse models for synucleinopathies not relying on overexpression. We report here two synucleinopathy mouse models, which are based on a triple alanine to proline mutation and a C-terminal truncation of αSyn, but do not overexpress the mutant protein when compared to the endogenous mouse protein. We knocked hαSyn TP or hαSynΔ119 (h stands for "human") into the murine αSyn locus. hαSynTP is a structure-based mutant with triple alanine to proline substitutions that favors oligomers, is neurotoxic and evokes PD-like symptoms in Drosophila melanogaster. hαSynΔ119 lacks 21 amino acids at the C-terminus, favors fibrillary aggregates and occurs in PD. Knocking-in of hαSyn TP or hαSynΔ119 into the murine αSyn locus places the mutant protein under the control of the endogenous regulatory elements while simultaneously disrupting the mαSyn gene. Mass spectrometry revealed that hαSyn TP and hαSynΔ119 mice produced 12 and 10 times less mutant protein, compared to mαSyn in wild type mice. We show phenotypes in 1 and 1.5 years old hαSyn TP and hαSynΔ119 mice, despite the lower levels of hαSynTP and hαSynΔ119 expression. Direct comparison of the two mouse models revealed many commonalities but also aspects unique to each model. Commonalities included strong immunoactive state, impaired olfaction and motor coordination deficits. Neither model showed DAergic neuronal loss. Impaired climbing abilities at 1 year of age and a deviant gait pattern at 1.5 years old were specific for hαSynΔ119 mice, while a compulsive behavior was exclusively detected in hαSyn TP mice starting at 1 year of age. We conclude that even at very moderate levels of expression the two αSyn variants evoke measurable and progressive deficiencies in mutant mice. The two transgenic mouse models can thus be suitable to study αSyn-variant-based pathology in vivo and test new therapeutic approaches.

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

Publications

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

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