Inhibition of fibrillization and accumulation of prefibrillar oligomers in mixtures of human and mouse alpha-synuclein.
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 alpha-synuclein. Two mutants of human alpha-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 alpha-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 alpha-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 alpha-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 alpha-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.
Rochet
J C
JC
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, USA.
Conway
K A
KA
Lansbury
P T
PT
D000409:Alanine / Q000235:genetics; D000682:Amyloid / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002850:Chromatography, Gel; D006801:Humans; D051379:Mice; D018625:Microscopy, Atomic Force; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D010300:Parkinson Disease / Q000378:metabolism; D011487:Protein Conformation; D017510:Protein Folding; D011498:Protein Precursors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D017550:Spectroscopy, Fourier Transform Infrared; D051843:Synucleins; D013912:Threonine / Q000235:genetics; D051844:alpha-Synuclein
D000682:Amyloid; D009419:Nerve Tissue Proteins; D011498:Protein Precursors; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein; D013912:Threonine; D000409:Alanine