alpha-Synuclein forms a complex with transcription factor Elk-1.
alpha-Synuclein has been identified as a component of Lewy bodies in Parkinson's disease and diffuse Lewy body disease, and glial cytoplasmic inclusions (GCIs) in multiple system atrophy (MSA). To explore the role of alpha-synuclein in the pathogenesis, we searched for molecules interacting with alpha-synuclein and discovered that GCIs are stained by anti-Elk-1 antibody. To seek the role of Elk-1 in synucleinopathies, we cotransfected alpha-synuclein and Elk-1 to cultured cells, and found small granular structure complexes where the two molecules colocalized. Moreover, alpha-synuclein and Elk-1 were co-immunoprecipitated from the cell lysates. For formation of the complex, the presence of both ETS and B-box domains of Elk-1 was required. Although there was no evidence of direct binding between alpha-synuclein and Elk-1, we discovered that alpha-synuclein and Elk-1 both bind to ERK-2, a MAP kinase. The effect of alpha-synuclein on the MAP kinase pathway was assessed using the Pathdetect system, which showed prominent attenuation of Elk-1 phosphorylation with alpha-synuclein, and especially A53T mutant. Our results suggest that alpha-synuclein reacts with the MAP kinase pathway, which might cause dysfunction of neurons and oligodendrocytes and lead to neurodegeneration in Parkinson's disease and MSA.
Iwata
A
A
Laboratory for CAG Repeat Diseases, Molecular Neuropathology Group, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan.
Miura
S
S
Kanazawa
I
I
Sawada
M
M
Nukina
N
N
D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D003594:Cytoplasmic Granules / Q000378:metabolism; D004268:DNA-Binding Proteins; D006801:Humans; D020961:Lewy Body Disease / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D046911:Macromolecular Substances; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D019578:Multiple System Atrophy / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011233:Precipitin Tests; D011485:Protein Binding / Q000235:genetics; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051843:Synucleins; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D051844:alpha-Synuclein; D050807:ets-Domain Protein Elk-1
D004268:DNA-Binding Proteins; C494112:ELK1 protein, human; C494113:Elk1 protein, mouse; D046911:Macromolecular Substances; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D014157:Transcription Factors; D051844:alpha-Synuclein; D050807:ets-Domain Protein Elk-1; D019950:Mitogen-Activated Protein Kinase 1