α-Synuclein and its A30P mutant affect actin cytoskeletal structure and dynamics

Vítor L. Sousa, Serena Bellani, Maila Giannandrea, Malikmohamed Yousuf, Flavia Valtorta, Jacopo Meldolesi, Evelina Chieregatti

Research output: Contribution to journalArticlepeer-review

Abstract

The function of α-synuclein, a soluble protein abundant in the brain and concentrated at presynaptic terminals, is still undefined. Yet, α-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 α-synuclein and its A30P mutant have different effects on actin polymerization. Wild-type α-synuclein binds actin, slows down its polymerization and accelerates its depolymerization, probably by monomer sequestration; A30P mutant α-synuclein increases the rate of actin polymerization and disrupts the cytoskeleton during reassembly of actin filaments. Consequently, in cells expressing mutant α-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 α-synuclein gene, electroporation of wild-type α-synuclein increases actin instability during remodeling, with growth of lamellipodia-like structures and apparent cell enlargement, whereas A30P α-synuclein induces discrete actin-rich foci during cytoskeleton reassembly. In conclusion, α-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.

Original languageEnglish
Pages (from-to)3725-3739
Number of pages15
JournalMolecular Biology of the Cell
Volume20
Issue number16
DOIs
Publication statusPublished - Aug 15 2009

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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