Journal
BIOCHEMISTRY
Volume 45, Issue 8, Pages 2599-2607Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bi051993m
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Funding
- Biotechnology and Biological Sciences Research Council [BB/A500061/1] Funding Source: Medline
- Medical Research Council [MC_U105178791, MC_U105184291] Funding Source: Medline
- MRC [MC_U105184291, MC_U105178791] Funding Source: UKRI
- Alzheimers Research UK [ART-PG1998-1] Funding Source: researchfish
- Biotechnology and Biological Sciences Research Council [BB/A500061/1] Funding Source: researchfish
- Medical Research Council [MC_U105184291, MC_U105178791] Funding Source: researchfish
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In humans, three genes encode the related alpha-, beta-, and gamma-synucleins, which function as lipid-binding proteins in vitro. They are being widely studied, mainly because of the central involvement of alpha-synuclein in a number of neurodegenerative diseases, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. In these diseases, the normally soluble alpha-synuclein assembles into abnormal filaments. Here, we have identified and characterized the synuclein gene family from the pufferfish Fugu rubripes. It consists of four genes, which encode alpha-, beta-, gamma 1-, and gamma 2-synucleins. They range from 113 to 127 amino acids in length and share many of the characteristics of human synucleins, including the presence of imperfect amino-terminal repeats of 11 amino acids, a hydrophobic middle region, and a negatively charged carboxy-terminus. All four synucleins are expressed in the Fugu brain. Recombinant Fugu synucleins exhibited differential liposome binding, which was strongest for alpha-synuclein, followed by beta-, gamma 2-, and gamma 1-synucleins. In assembly experiments, Fugu alpha-, gamma 1-, and gamma 2-synucleins formed filaments more readily than human alpha-synuclein. Fugu beta-synuclein, by contrast, failed to assemble in bulk. Filament assembly of synucleins was directly proportional to their degree of hydrophobicity and their tendency to form beta-sheet structure, and correlated inversely with their net charge.
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