α-synuclein strains that cause distinct pathologies differentially inhibit proteasome.

Genjiro Suzuki,Ryu Katsumata,Masato Hosokawa,Masato Hasegawa,Shin-Ichi Hisanaga,Takashi Nonaka,Yasushi Saeki,Sei Imura

doi:10.7554/elife.56825

Genjiro Suzuki, Ryu Katsumata + Show 6 more

Open Access

https://doi.org/10.7554/elife.56825

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Abstract

Abnormal α-synuclein aggregation has been implicated in several diseases and is known to spread in a prion-like manner. There is a relationship between protein aggregate structure (strain) and clinical phenotype in prion diseases, however, whether differences in the strains of α-synuclein aggregates account for the different pathologies remained unclear. Here, we generated two types of α-synuclein fibrils from identical monomer and investigated their seeding and propagation ability in mice and primary-cultured neurons. One α-synuclein fibril induced marked accumulation of phosphorylated α-synuclein and ubiquitinated protein aggregates, while the other did not, indicating the formation of α-synuclein two strains. Notably, the former α-synuclein strain inhibited proteasome activity and co-precipitated with 26S proteasome complex. Further examination indicated that structural differences in the C-terminal region of α-synuclein strains lead to different effects on proteasome activity. These results provide a possible molecular mechanism to account for the different pathologies induced by different α-synuclein strains.

Highlights

Misfolding and aggregation of normally soluble proteins are common pathological features of many neurodegenerative diseases, including Alzheimer’s, Parkinson’s, Creutzfeldt–Jacob and Huntington’s diseases (Ross & Poirier, 2004)
In Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), α-synuclein pathologies are mainly observed in neurons in the form of Lewy bodies (LBs) and Lewy neurites (LNs) (Baba et al, 1998), while glial cytoplasmic inclusions (GCIs) are seen in oligodendrocytes in multiple system atrophy (MSA)
The differences of Thioflavin T fluorescence and Congo red binding of these α-synuclein fibrils suggested that these fibrils have a different structures each other

Summary

Introduction

Misfolding and aggregation of normally soluble proteins are common pathological features of many neurodegenerative diseases, including Alzheimer’s, Parkinson’s, Creutzfeldt–Jacob and Huntington’s diseases (Ross & Poirier, 2004). The variety of strains that can be differentiated in terms of the clinical signs, incubation period after inoculation, and the vacuolation lesion profiles in the brain of affected animals is due to structural differences of PrP aggregates, as identified by biochemical analyses including glycosylation profile, electrophoretic mobility, protease resistance, and sedimentation. We prepared two α-synuclein assemblies from identical wild-type α-synuclein monomer under different conditions, and established that they have distinct conformations, i.e., we succeeded to generating two α-synuclein fibrils from the same monomer We examined their seeding abilities to convert endogenous soluble α-synuclein monomers into phosphorylated aggregates in mice and primary-cultured neurons, indicating the formation of two α-synuclein strains. These results provide a possible molecular mechanism to account for the different lesions induced by distinct α-synuclein strains

Results

Discussion

Materials and methods