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.
Laboratory for CAG Repeat Diseases, Molecular Neuropathology Group, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan.
A
A
Iwata
S
S
Miura
I
I
Kanazawa
M
M
Sawada
N
N
Nukina
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