Preserved proteinase K-resistant core after amplification of alpha-synuclein aggregates: Implication to disease-related structural study.

Preserved proteinase K-resistant core after amplification of alpha-synuclein aggregates: Implication to disease-related structural study.

Publication date: Nov 27, 2019

Many pathological proteins related to neurodegenerative diseases are misfolded, aggregating to form amyloid fibrils during pathogenesis. One of the pathological proteins, alpha-synuclein (?-syn), accumulates in the brains of Parkinson disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), which are designated as synucleinopathies. Recently, structural properties of abnormal accumulated proteins are suggested to determine the disease phenotype. However, the biochemical and structural characteristics of those accumulated proteins are still poorly understood. We previously reported the sequence and seed-structure-dependent polymorphic fibrils of ?-syn and the polymorphism was identified by proteinase K-resistant cores determined by mass spectrometry (MS) analysis. In this study, we applied this method to analyze ?-syn aggregates of MSA and DLB. To perform MS analysis on proteinase K-resistant cores, we first performed amplification of ?-syn aggregates by seeding reaction and protein misfolding cyclic amplification (PMCA) to obtain a sufficient amount of aggregates. Using SDS insoluble fraction of the disease brain, we successfully amplified enough ?-syn aggregates for MS analysis. We differentiated between mouse and human ?-syn aggregates by MS analysis on proteinase K-resistant cores of the aggregates before and after amplification. The results suggest that structural properties of amplified ?-syn fibrils are preserved after PMCA and these methods can be applicable in the study of pathological proteins of the neurodegenerative disorders.

Yoshinaga, S., Yamanaka, T., Miyazaki, H., Okuzumi, A., Hiyama, A., Murayama, S., and Nukina, N. Preserved proteinase K-resistant core after amplification of alpha-synuclein aggregates: Implication to disease-related structural study. 23149. 2019 Biochem Biophys Res Commun.

Concepts Keywords
Amyloid Synucleinopathy
Biochemical Neuropathology
Brain Peripheral membrane proteins
Dementia Neurological disorders
Fibrils Lewy body dementia
Lewy Bodies Proteins
Mass Spectrometry Organ systems
Misfolding Branches of biology
Multiple System Atrophy MS
Neurodegenerative Diseases Parkinson’s disease
Neurodegenerative Disorders Alpha-synuclein
Parkinson Neurodegeneration
Pathogenesis Alpha
Phenotype
Polymorphic
Polymorphism
SDS
Seed Structure

Semantics

Type Source Name
drug DRUGBANK Sodium lauryl sulfate
disease MESH multiple system atrophy
disease MESH dementia
pathway KEGG Parkinson disease
disease MESH Parkinson disease
pathway REACTOME Neurodegenerative Diseases
disease MESH neurodegenerative diseases

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