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Functional protein kinase arrays reveal inhibition of p‐21‐activated kinase 4 by α‐synuclein oligomers
Author(s) -
Danzer Karin M.,
Schnack Cathrin,
Sutcliffe Andrew,
Hengerer Bastian,
Gillardon Frank
Publication year - 2007
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2007.04933.x
Subject(s) - autophosphorylation , alpha synuclein , kinase , microbiology and biotechnology , protein kinase a , biology , biochemistry , phosphorylation , synuclein , genetically modified mouse , chemistry , transgene , parkinson's disease , medicine , disease , gene
There is increasing evidence that aggregation of α‐synuclein contributes to the functional and structural deterioration in the CNS of Parkinson’s disease patients and transgenic animal models. α‐Synuclein binds to various cellular proteins and aggregated α‐synuclein species may affect their physiological function. In the present study, we used protein arrays spotted with 178 active human kinases for a large‐scale analysis of the effects of recombinant α‐synuclein on kinase activities. Incubation with globular α‐synuclein oligomers significantly inhibited autophosphorylation of p21‐activated kinase (PAK4) compared to treatment with monomeric α‐synuclein or β‐synuclein. A concentration‐dependent inhibition was also observed in a solution‐based kinase assay. To show in vivo relevance, we analyzed brainstem protein extracts from α‐synuclein (A30P) transgenic mice where accumulation of α‐synuclein oligomers has been demonstrated. By immunoblotting using a phospho‐specific antibody, we detected a significant decline in phosphorylation of LIM kinase 1, a physiological substrate for PAK4. Suppression of PAK activity by amyloid‐β oligomers has been reported in Alzheimer’s disease. Thus, PAKs may represent a target for various neurotoxic protein oligomers, and signaling deficits may contribute to the behavioral defects in chronic neurodegenerative diseases.