Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease.
Two mutations in the gene encoding alpha-synuclein have been linked to early-onset Parkinson's disease (PD). alpha-Synuclein is a component of Lewy bodies, the fibrous cytoplasmic inclusions characteristic of nigral dopaminergic neurons in the PD brain. This connection between genetics and pathology suggests that the alpha-synuclein mutations may promote PD pathogenesis by accelerating Lewy body formation. To test this, we studied alpha-synuclein folding and aggregation in vitro, in the absence of other Lewy body-associated molecules. We demonstrate here that both mutant forms of alpha-synuclein (A53T and A30P) are, like wild-type alpha-synuclein (WT), disordered in dilute solution. However, at higher concentrations, Lewy body-like fibrils and discrete spherical assemblies are formed; most rapidly by A53T. Thus, mutation-induced acceleration of alpha-synuclein fibril formation may contribute to the early onset of familial PD.
Conway
K A
KA
Center for Neurologic Diseases, Brigham and Women's Hospital and Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Harper
J D
JD
Lansbury
P T
PT
D017668:Age of Onset; D000409:Alanine; D019943:Amino Acid Substitution; D002942:Circular Dichroism; D006801:Humans; D016631:Lewy Bodies / Q000473:pathology / Q000648:ultrastructure*; D018625:Microscopy, Atomic Force; D008854:Microscopy, Electron; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics* / Q000648:ultrastructure; D009474:Neurons / Q000473:pathology*; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D010750:Phosphoproteins / Q000235:genetics; D017354:Point Mutation; D011994:Recombinant Proteins / Q000737:chemistry / Q000648:ultrastructure; D013378:Substantia Nigra / Q000473:pathology; D051843:Synucleins; D013912:Threonine; D051844:alpha-Synuclein
D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D011994:Recombinant Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D013912:Threonine; D000409:Alanine