alpha-Synuclein and its disease-related mutants interact differentially with the microtubule protein tau and associate with the actin cytoskeleton.
alpha-Synuclein is a primarily neuronal protein that is enriched at the pre-synapse. alpha-Synuclein and the microtubule binding protein tau have been implicated in neurodegenerative diseases. alpha-Synuclein is known to associate with phospholipid vesicles, regulates dopamine metabolism and exhibits chaperone activity, but its main role remains largely unknown. Furthermore, knowledge on its interactions and post-translational modifications is essential for a molecular understanding of alpha-synucleinopathies. We investigated alpha-synuclein mutations, causative for autosomal dominant forms of Parkinson's disease (A30P, A53T and E46K), and phosphorylation mutants at serine 129 (S129A and S129D) using fluorescently labelled alpha-synuclein, actin and tau. The investigation of colocalization, and protein-protein interactions by Förster resonance energy transfer and fluorescence lifetime imaging showed that alpha-synuclein associates with the actin cytoskeleton and interacts with tau. The A30P mutation and cytoskeletal destabilization decreased this interaction. Given the concurrent loss of membrane binding by this mutation, we propose a membrane-bound functional complex with tau that might involve the actin cytoskeleton.
Esposito
Alessandro
A
Cell Biophysics Group at the European Neuroscience Institute-Göttingen, Waldweg, 33, 37073 Göttingen, Germany. aesposito@quantitative-microscopy.org
Dohm
Christoph P
CP
Kermer
Pawel
P
Bähr
Mathias
M
Wouters
Fred S
FS
D000199:Actins / Q000235:genetics / Q000378:metabolism*; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D016466:CHO Cells; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006224:Cricetinae; D003412:Cricetulus; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008856:Microscopy, Fluorescence; D009154:Mutation / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism*; D020734:Parkinsonian Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D010766:Phosphorylation; D011485:Protein Binding / Q000235:genetics; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D000199:Actins; D051844:alpha-Synuclein; D016875:tau Proteins