Crosstalk Between Alpha-Synuclein and Other Human and Non-Human Amyloidogenic Proteins: Consequences for Amyloid Formation in Parkinson’s Disease

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

Communications Biology ◽

10.1038/s42003-019-0598-9 ◽

2019 ◽

Vol 2 (1) ◽

Cited By ~ 15

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.

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Bioinorganic Chemistry of Parkinson’s Disease: Structural Determinants for the Copper-Mediated Amyloid Formation of Alpha-Synuclein

Inorganic Chemistry ◽

10.1021/ic1016752 ◽

2010 ◽

Vol 49 (22) ◽

pp. 10668-10679 ◽

Cited By ~ 85

Author(s):

Andrés Binolfi ◽

Esaú E. Rodriguez ◽

Daniela Valensin ◽

Nicola D’Amelio ◽

Emiliano Ippoliti ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Bioinorganic Chemistry ◽

Alpha Synuclein ◽

Amyloid Formation ◽

Structural Determinants

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Cross-talk between amyloidogenic proteins in type-2 diabetes and Parkinson’s disease

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1610371113 ◽

2016 ◽

Vol 113 (44) ◽

pp. 12473-12477 ◽

Cited By ~ 61

Author(s):

Istvan Horvath ◽

Pernilla Wittung-Stafshede

Keyword(s):

Type 2 Diabetes ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cross Reactivity ◽

Amyloid Formation ◽

Islet Amyloid ◽

Amyloid Fibers ◽

Amyloidogenic Proteins

In type-2 diabetes (T2D) and Parkinson’s disease (PD), polypeptide assembly into amyloid fibers plays central roles: in PD, α-synuclein (aS) forms amyloids and in T2D, amylin [islet amyloid polypeptide (IAPP)] forms amyloids. Using a combination of biophysical methods in vitro we have investigated whether aS, IAPP, and unprocessed IAPP, pro-IAPP, polypeptides can cross-react. Whereas IAPP forms amyloids within minutes, aS takes many hours to assemble into amyloids and pro-IAPP aggregates even slower under the same conditions. We discovered that preformed amyloids of pro-IAPP inhibit, whereas IAPP amyloids promote, aS amyloid formation. Amyloids of aS promote pro-IAPP amyloid formation, whereas they inhibit IAPP amyloid formation. In contrast, mixing of IAPP and aS monomers results in coaggregation that is faster than either protein alone; moreover, pro-IAPP can incorporate aS monomers into its amyloid fibers. From this intricate network of cross-reactivity, it is clear that the presence of IAPP can accelerate aS amyloid formation. This observation may explain why T2D patients are susceptible to developing PD.

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The Hsc70 Disaggregation Machinery Removes Monomer Units Directly from α-Synuclein Fibril Ends

10.1101/2020.11.02.365825 ◽

2020 ◽

Cited By ~ 1

Author(s):

Matthias M. Schneider ◽

Saurabh Gautam ◽

Therese W. Herling ◽

Ewa Andrzejewska ◽

Georg Krainer ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neurodegenerative Diseases ◽

De Novo ◽

Dissociation Constants ◽

Cellular Protein ◽

Alpha Synuclein ◽

Amyloid Formation ◽

Nucleotide Exchange ◽

Wide Range

AbstractMolecular chaperones contribute to the maintenance of cellular protein homeostasis through a wide range of mechanisms, including the assistance of de novo protein folding, the rescue of misfolded proteins, and the prevention of amyloid formation. Chaperones of the Hsp70 family have a striking capability of disaggregating otherwise irreversible aggregate structures such as amyloid fibrils that accumulate during the development of neurodegenerative diseases. However, the mechanisms of this key emerging functionality remain largely unknown. Here, we bring together microfluidic measurements with kinetic analysis and show that that the Hsp70 protein heat chock complement Hsc70 together with its two co-chaperones DnaJB1 and the nucleotide exchange factor Apg2 is able to completely reverse the aggregation process of alpha-synuclein, associated with Parkinson’s disease, back to its soluble monomeric state. Moreover, we show that this reaction proceeds with first order kinetics in a process where monomer units are taken off directly from the fibril ends. Our results demonstrate that all components of the chaperone triad are essential for fibril disaggregation. Lastly, we quantify the interactions between the three chaperones as well as between the chaperones and the fibrils in solution, yielding both binding stoichiometries and dissociation constants. Crucially, we find that the stoichiometry of Hsc70 binding to fibrils suggests Hsc70 clustering at the fibril ends. Taken together, our results show that the mechanism of action of the Hsc70–DnaJB1–Apg2 chaperone system in disaggregating α-synuclein fibrils involves the removal of monomer units without any intermediate fragmentation steps. These findings are fundamental to our understanding of the suppression of amyloid proliferation early in life and the natural clearance mechanisms of fibrillar deposits in Parkinson’s disease, and inform on the possibilities and limitations of this strategy in the development of therapeutics against synucleinopathies and related neurodegenerative diseases.

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