title: Incorporation of cofilin into rods depends on disulfide intermolecular bonds: implications for actin regulation and neurodegenerative disease.
abstract: Rod-shaped aggregates ("rods"), containing equimolar actin and the actin dynamizing protein cofilin, appear in neurons following a wide variety of potentially oxidative stress: simulated microischemia, cofilin overexpression, and exposure to peroxide, excess glutamate, or the dimer/trimer forms of amyloid-β peptide (Aβd/t), the most synaptotoxic Aβ species. These rods are initially reversible and neuroprotective, but if they persist in neurites, the synapses degenerate without neurons dying. Herein we report evidence that rod formation depends on the generation of intermolecular disulfide bonds in cofilin. Of four Cys-to-Ala cofilin mutations expressed in rat E18 hippocampal neurons, only the mutant incapable of forming intermolecular bonds (CC39,147AA) has significantly reduced ability to incorporate into rods. Rod regions show unusually high oxidation levels. Rods, isolated from stressed neurons, contain dithiothreitol-sensitive multimeric forms of cofilin, predominantly dimer. Oligomerization of cofilin in cells represents one more mechanism for regulating the actin dynamizing activity of cofilin and probably underlies synaptic loss.
authors.affiliation: Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523-1870, USA. bwb@lamar.colostate.edu
authors.forename: Barbara W
authors.initials: BW
authors.lastname: Bernstein
authors.forename: Alisa E
authors.initials: AE
authors.lastname: Shaw
authors.forename: Laurie S
authors.initials: LS
authors.lastname: Minamide
authors.forename: Chi W
authors.initials: CW
authors.lastname: Pak
authors.forename: James R
authors.initials: JR
authors.lastname: Bamburg
mesh_terms: D051339:Actin Depolymerizing Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000199:Actins / Q000502:physiology*; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002645:Chickens; D004220:Disulfides / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D055503:Protein Multimerization / Q000235:genetics; D051381:Rats; D013552:Swine
chemical_list: D051339:Actin Depolymerizing Factors; D000199:Actins; D004220:Disulfides