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Sequence- and seed-structure-dependent polymorphic fibrils of alpha-synuclein
- Source :
- Biochimica et biophysica acta. Molecular basis of disease. 1865(6)
- Publication Year :
- 2018
-
Abstract
- Synucleinopathies comprise a diverse group of neurodegenerative diseases including Parkinson's disease (PD), dementia with Lewy bodies, and multiple system atrophy. These share a common pathological feature, the deposition of alpha-synuclein (a-syn) in neurons or oligodendroglia. A-syn is highly conserved in vertebrates, but the primary sequence of mouse a-syn differs from that of human at seven positions. However, structural differences of their aggregates remain to be fully characterized. In this study, we found that human and mouse a-syn aggregated in vitro formed morphologically distinct amyloid fibrils exhibiting twisted and straight structures, respectively. Furthermore, we identified different protease-resistant core regions, long and short, in human and mouse a-syn aggregates. Interestingly, among the seven unconserved amino acids, only A53T substitution, one of the familial PD mutations, was responsible for structural conversion to the straight-type. Finally, we checked whether the structural differences are transmissible by seeding and found that human a-syn seeded with A53T aggregates formed straight-type fibrils with short protease-resistant cores. These results suggest that a-syn aggregates form sequence-dependent polymorphic fibrils upon spontaneous aggregation but become seed structure-dependent upon seeding.
- Subjects :
- 0301 basic medicine
Amyloid
Recombinant Fusion Proteins
Genetic Vectors
Gene Expression
Protein aggregation
Fibril
03 medical and health sciences
chemistry.chemical_compound
Mice
Protein Aggregates
0302 clinical medicine
Species Specificity
medicine
Escherichia coli
Animals
Humans
Amino Acid Sequence
Cloning, Molecular
Molecular Biology
Gene
Synucleinopathies
chemistry.chemical_classification
Alpha-synuclein
Sequence Homology, Amino Acid
Dementia with Lewy bodies
Chemistry
medicine.disease
In vitro
Amino acid
Cell biology
030104 developmental biology
nervous system
Amino Acid Substitution
alpha-Synuclein
Molecular Medicine
Sequence Alignment
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 1879260X
- Volume :
- 1865
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Biochimica et biophysica acta. Molecular basis of disease
- Accession number :
- edsair.doi.dedup.....796f4c711934cc7a1a0400e8527b0de6