{alpha}-synuclein and its A30P mutant affect actin cytoskeletal structure and dynamics.
The function of alpha-synuclein, a soluble protein abundant in the brain and concentrated at presynaptic terminals, is still undefined. Yet, alpha-synuclein overexpression and the expression of its A30P mutant are associated with familial Parkinson's disease. Working in cell-free conditions, in two cell lines as well as in primary neurons we demonstrate that alpha-synuclein and its A30P mutant have different effects on actin polymerization. Wild-type alpha-synuclein binds actin, slows down its polymerization and accelerates its depolymerization, probably by monomer sequestration; A30P mutant alpha-synuclein increases the rate of actin polymerization and disrupts the cytoskeleton during reassembly of actin filaments. Consequently, in cells expressing mutant alpha-synuclein, cytoskeleton-dependent processes, such as cell migration, are inhibited, while exo- and endocytic traffic is altered. In hippocampal neurons from mice carrying a deletion of the alpha-synuclein gene, electroporation of wild-type alpha-synuclein increases actin instability during remodeling, with growth of lamellipodia-like structures and apparent cell enlargement, whereas A30P alpha-synuclein induces discrete actin-rich foci during cytoskeleton reassembly. In conclusion, alpha-synuclein appears to play a major role in actin cytoskeletal dynamics and various aspects of microfilament function. Actin cytoskeletal disruption induced by the A30P mutant might alter various cellular processes and thereby play a role in the pathogenesis of neurodegeneration.
Sousa
Vítor L
VL
Department of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
Bellani
Serena
S
Giannandrea
Maila
M
Yousuf
Malikmohamed
M
Valtorta
Flavia
F
Meldolesi
Jacopo
J
Chieregatti
Evelina
E
D000199:Actins / Q000378:metabolism* / Q000648:ultrastructure; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism / Q000648:ultrastructure; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D017354:Point Mutation; D011485:Protein Binding; D011554:Pseudopodia / Q000378:metabolism / Q000648:ultrastructure; D053778:Thiazolidines / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
D000199:Actins; D019086:Bridged Bicyclo Compounds, Heterocyclic; D053778:Thiazolidines; D051844:alpha-Synuclein; C037067:latrunculin A