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Inhibition of Fibrillization and Accumulation of Prefibrillar Oligomers in Mixtures of Human and Mouse α-Synuclein

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    Inhibition of Fibrillization and Accumulation of Prefibrillar Oligomers in Mixtures of Human and Mouse α-Synuclein†
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    Morris K. Udall Parkinson's Disease Research Center of Excellence, Center for Neurologic Diseases, Brigham and Women's Hospital, and Department of Neurology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115
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    Biochemistry

    Cite this: Biochemistry 2000, 39, 35, 10619–10626
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    https://doi.org/10.1021/bi001315u
    Published August 10, 2000
    Copyright © 2000 American Chemical Society
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    Abstract

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    Parkinson's disease (PD) is a neurodegenerative disorder attributed to the loss of dopaminergic neurons from the substantia nigra. Some surviving neurons are characterized by cytoplasmic Lewy bodies, which contain fibrillar α-synuclein. Two mutants of human α-synuclein (A53T and A30P) have been linked to early-onset, familial PD. Oligomeric forms of these mutants accumulate more rapidly and/or persist for longer periods of time than oligomeric, human wild-type α-synuclein (WT), suggesting a link between oligomerization and cell death. The amino acid sequences of the mouse protein and WT differ at seven positions. Mouse α-synuclein, like A53T, contains a threonine residue at position 53. We have assessed the conformational properties and fibrillogenicity of the murine protein. Like WT and the two PD mutants, mouse α-synuclein adopts a “natively unfolded” or disordered structure. However, at elevated concentrations, the mouse protein forms amyloid fibrils more rapidly than WT, A53T, or A30P. The fibrillization of mouse α-synuclein is slowed by WT and A53T. Inhibition of fibrillization leads to the accumulation of nonfibrillar, potentially toxic oligomers. The results are relevant to the interpretation of the phenotypes of transgenic animal models of PD and suggest a novel approach for testing the cause and effect relationship between fibrillization and neurodegeneration.

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    †

     This work was funded in part by grants from the National Institutes of Health (AG08470 and AG14366) and a Zenith Award from the Alzheimer's Association. J.-C.R. was supported by fellowships from the Alberta Heritage Foundation for Medical Research and the Human Frontier Science Program.

    *

     To whom correspondence should be addressed. Telephone:  (617) 525-5260. Fax:  (617) 525-5252. E-mail:  [email protected].

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    Cite this: Biochemistry 2000, 39, 35, 10619–10626
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    https://doi.org/10.1021/bi001315u
    Published August 10, 2000
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