A Triple-Emission Fluorescent Probe Reveals Distinctive Amyloid Fibrillar Polymorphism of Wild-Type α-Synuclein and Its Familial Parkinson’s Disease Mutants

Biochemistry ◽  
2009 ◽  
Vol 48 (31) ◽  
pp. 7465-7472 ◽  
Author(s):  
M. Soledad Celej ◽  
Wouter Caarls ◽  
Alexander P. Demchenko ◽  
Thomas M. Jovin
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Fluorescent Probe ◽  
Wild Type ◽  
Familial Parkinson’S Disease

scholarly journals Familial Parkinson's Disease Mutant E46K α-Synuclein Localizes to Membranous Structures, Forms Aggregates, and Induces Toxicity in Yeast Models

2011 ◽  
Vol 2011 ◽  
pp. 1-14 ◽  
Author(s):  
Michael Fiske ◽  
Michael White ◽  
Stephanie Valtierra ◽  
Sara Herrera ◽  
Keith Solvang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Plasma Membrane ◽  
Mutant Form ◽  
Phospholipid Membrane ◽  
Endomembrane System ◽  
Wild Type ◽  
Significant Toxicity ◽  
Familial Parkinson’S Disease

In Parkinson’s disease (PD), midbrain dopaminergic neuronal death is linked to the accumulation of aggregated α-synuclein. The familial PD mutant form of α-synuclein, E46K, has not been thoroughly evaluated yet in an organismal model system. Here, we report that E46K resembled wild-type (WT) α-synuclein in Saccharomyces cerevisiae in that it predominantly localized to the plasma membrane, and it did not induce significant toxicity or accumulation. In contrast, in Schizosaccharomyces pombe, E46K did not associate with the plasma membrane. Instead, in one strain, it extensively aggregated in the cytoplasm and was as toxic as WT. Remarkably, in another strain, E46K extensively associated with the endomembrane system and was more toxic than WT. Our studies recapitulate and extend aggregation and phospholipid membrane association properties of E46K previously observed in vitro and cell culture. Furthermore, it supports the notion that E46K generates toxicity partly due to increased association with endomembrane systems within cells.

scholarly journals Alpha-synuclein stepwise aggregation reveals features of an early onset mutation in Parkinson’s disease

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Guilherme A. P. de Oliveira ◽  
Jerson L. Silva
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Early Onset ◽  
Point Mutations ◽  
Alpha Synuclein ◽  
Amyloid Formation ◽  
Wild Type ◽  
Cryo Electron Microscopy ◽  
Familial Parkinson’S Disease ◽  
Direct Detector

Abstract Amyloid formation is a process involving interconverting protein species and results in toxic oligomers and fibrils. Aggregated alpha-synuclein (αS) participates in neurodegenerative maladies, but a closer understanding of the early αS polymerization stages and polymorphism of heritable αS variants is sparse still. Here, we distinguished αS oligomer and protofibril interconversions in Thioflavin T polymerization reactions. The results support a hypothesis reconciling the nucleation-polymerization and nucleation-conversion-polymerization models to explain the dissimilar behaviors of wild-type and the A53T mutant. Cryo-electron microscopy with a direct detector shows the polymorphic nature of αS fibrils formed by heritable A30P, E46K, and A53T point mutations. By showing that A53T rapidly nucleates competent species, continuously elongates fibrils in the presence of increasing amounts of seeds, and overcomes wild-type surface requirements for growth, our findings place A53T with features that may explain the early onset of familial Parkinson’s disease cases bearing this mutation.

scholarly journals Protection Against Oxidative Stress-Induced Neurodegeneration by a Modulator for DJ-1, the Wild-Type of Familial Parkinson’s Disease-Linked PARK7

2009 ◽  
Vol 109 (3) ◽  
pp. 463-468 ◽  
Author(s):  
Takashi Yanagida ◽  
Yoshihisa Kitamura ◽  
Koichiro Yamane ◽  
Kazunori Takahashi ◽  
Kazuyuki Takata ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Wild Type ◽  
Familial Parkinson’S Disease

scholarly journals The hereditary mutation G51D unlocks a distinct fibril strain transmissible to wild-type α-synuclein

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yunpeng Sun ◽  
Houfang Long ◽  
Wencheng Xia ◽  
Kun Wang ◽  
Xia Zhang ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Strain Selection ◽  
Wild Type ◽  
Distinct Structure ◽  
The Cross ◽  
Familial Parkinson’S Disease ◽  
Selection Of

Abstractα-Synuclein (α-Syn) can form different fibril strains with distinct polymorphs and neuropathologies, which is associated with the clinicopathological variability in synucleinopathies. How different α-syn fibril strains are produced and selected under disease conditions remains poorly understood. In this study, we show that the hereditary mutation G51D induces α-syn to form a distinct fibril strain in vitro. The cryogenic electron microscopy (cryo-EM) structure of the G51D fibril strain was determined at 2.96 Å resolution. The G51D fibril displays a relatively small and extended serpentine fold distinct from other α-syn fibril structures. Moreover, we show by cryo-EM that wild-type (WT) α-syn can assembly into the G51D fibril strain via cross-seeding with G51D fibrils. Our study reveals a distinct structure of G51D fibril strain triggered by G51D mutation but feasibly adopted by both WT and G51D α-syn, which suggests the cross-seeding and strain selection of WT and mutant α-syn in familial Parkinson’s disease (fPD).

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