Anionic Micelles and Vesicles Induce Tau Fibrillization in Vitro

Chirita, Carmen N.; Necula, Mihaela; Kuret, Jeff

doi:10.1074/jbc.m301663200

Cited by 220 publications

(273 citation statements)

References 57 publications

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“…These studies suggest that FAs play a pivotal role as nucleates in the self-assembly of misfolded proteins. Although the precise mechanism of how lipid molecules accelerate protein aggregation has not been elucidated, it has been proposed that lipid-bound proteins change their conformation or anionic surfaces, presenting as micelles or vesicles, which can serve to nucleate aggregate formation (18,34,35). We confirmed that apo-SOD1s or heattreated holo-SOD1 mutants were bound to oleic acid (Fig.…”

Section: Discussionsupporting

confidence: 71%

Unsaturated Fatty Acids Induce Cytotoxic Aggregate Formation of Amyotrophic Lateral Sclerosis-linked Superoxide Dismutase 1 Mutants

Kim¹,

Nakatomi

Akagi

et al. 2005

Journal of Biological Chemistry

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Formation of misfolded protein aggregates is a remarkable hallmark of various neurodegenerative diseases including Alzheimer disease, Parkinson disease, Huntington disease, prion encephalopathies, and amyotrophic lateral sclerosis (ALS). Superoxide dismutase 1 (SOD1) immunoreactive inclusions have been found in the spinal cord of ALS animal models and patients, implicating the close involvement of SOD1 aggregates in ALS pathogenesis. Here we examined the molecular mechanism of aggregate formation of ALS-related SOD1 mutants in vitro. We found that long-chain unsaturated fatty acids (FAs) promoted aggregate formation of SOD1 mutants in both dose-and time-dependent manners. Metal-deficient SOD1s, wild-type, and mutants were highly oligomerized compared with holo-SOD1s by incubation in the presence of unsaturated FAs. Oligomerization of SOD1 is closely associated with its structural instability. Heat-treated holo-SOD1 mutants were readily oligomerized by the addition of unsaturated FAs, whereas wild-type SOD1 was not. The monounsaturated FA, oleic acid, directly bound to SOD1 and was characterized by a solid-phase FA binding assay using oleate-Sepharose. The FA binding characteristics were closely correlated with the oligomerization propensity of SOD1 proteins, which indicates that FA binding may change SOD1 conformation in a way that favors the formation of aggregates. High molecular mass aggregates of SOD1 induced by FAs have a granular morphology and show significant cytotoxicity. These findings suggest that SOD1 mutants gain FA binding abilities based on their structural instability and form cytotoxic granular aggregates. Amyotrophic lateral sclerosis (ALS)1 is a progressive and fatal neurodegenerative disorder that mainly affects motor neurons in the brain stem and spinal cord. Approximately 10% of ALS patients are familial cases, with autosomal dominant inheritance. More than 90 different mutations in the gene coding for superoxide dismutase 1 (SOD1) have been identified in about 20% of familial ALS (FALS) families (1, 2). Although the molecular mechanisms of selective motor neuron degeneration by SOD1 mutants in FALS remain largely unknown, common pathological features of conformational diseases, as evidenced by SOD1 immunoreactive inclusions, are found in the spinal cord of ALS patients and in the SOD1 mutant FALS mouse model (3-8). The characteristics of FALS resemble those of many other neurodegenerative diseases in which a causative protein undergoes a conformational rearrangement, which endows it with a tendency to aggregate and form deposits within affected tissues.SOD1 is a 32-kDa homodimeric enzyme that decreases the intracellular concentration of superoxide radicals by catalyzing their dismutation to O 2 and H 2 O 2 . ALS-linked mutations of SOD1 are distributed throughout the primary and tertiary structures, and most mutations appear unrelated to the dismutase activity. Many biochemical and biophysical studies have reported that SOD1 mutants are structurally unstable compared with wild-type forms (...

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Section: Discussionsupporting

confidence: 71%

Unsaturated Fatty Acids Induce Cytotoxic Aggregate Formation of Amyotrophic Lateral Sclerosis-linked Superoxide Dismutase 1 Mutants

Kim¹,

Nakatomi

Akagi

et al. 2005

Journal of Biological Chemistry

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“…Consistent with earlier observations (47) the CMC for arachidonic acid in assembly buffer alone was measured as 236 Ϯ 12 M, which was well above the concentration required for acceleration of ␣-synuclein fibrillization. When CMC was measured in assembly buffer complete with ␣-synuclein at 15 M, however, the CMC decreased to 10.3 Ϯ 4.8 M. This magnitude of CMC depression is similar to that induced by tau protein (48). These data show that fatty acids such as arachidonic acid aggregate to form micelles at much lower concentrations in the presence of ␣-synuclein than in its absence.…”

Section: Efficient Induction Of ␣-Synucleinmentioning

confidence: 49%

“…Depression of the CMC for anionic detergents is regularly observed in the presence of cationic electrolytes (66) including proteins such as tau (48). But whereas tau protein contains a net positive charge at assay pH, ␣-synuclein is negatively charged.…”

Section: Discussionmentioning

confidence: 99%

Rapid Anionic Micelle-mediated α-Synuclein Fibrillization in Vitro

Necula¹,

Chirita²,

Kuret

2003

Journal of Biological Chemistry

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Parkinson's disease is characterized by the aggregation of ␣-synuclein into filamentous forms within affected neurons of the basal ganglia. Fibrillization of purified recombinant ␣-synuclein is inefficient in vitro but can be enhanced by the addition of various agents including glycosaminoglycans and polycations. Here we report that fatty acids and structurally related anionic detergents greatly accelerate fibrillization of recombinant ␣-synuclein at low micromolar concentrations with lag times as short as 11 min and apparent first order growth rate constants as fast as 10.4 h ؊1 . All detergents and fatty acids were micellar at active concentrations because of an ␣-synuclein-dependent depression of their critical micelle concentrations. Other anionic surfaces, such as those supplied by anionic phospholipid vesicles, also induced ␣-synuclein fibrillization, with resultant filaments originating from their surface. These data suggest that anionic surfaces presented as micelles or vesicles can serve to nucleate ␣-synuclein fibrillization, that this mechanism underlies the inducer activity of anionic surfactants, and that anionic membranes may serve this function in vivo.

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“…These inducers, which include anionic surfactant micelles, promote heterogeneous nucleation (i.e., nucleation owing to the presence of foreign particles) on their surfaces from which tau filaments then extend in an elongation reaction [5][6][7]. Tau fibrillization antagonists identified by in *Corresponding Author: Jeff Kuret, Ph.D., Center for Molecular Neurobiology, 1060 Carmack Rd., Columbus, OH 43210, Fax: 614-292-5379, Email address: kuret.3@osu.edu (J. Kuret).…”

Section: Introductionmentioning

confidence: 99%

Potent inhibition of tau fibrillization with a multivalent ligand

Honson

Jensen

Darby

et al. 2007

Biochemical and Biophysical Research Communications

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Small-molecule inhibitors of tau fibrillization are under investigation as tools for interrogating the tau aggregation pathway and as potential therapeutic agents for Alzheimer's disease. Established inhibitors include thiacarbocyanine dyes, which can inhibit recombinant tau fibrillization in the presence of anionic surfactant aggregation inducers. In an effort to increase inhibitory potency, a cyclic bis-thiacarbocyanine molecule containing two thiacarbocyanine moieties was synthesized and characterized with respect to tau fibrillization inhibitory activity by electron microscopy and ligand aggregation state by absorbance spectroscopy. Results showed that the inhibitory activity of the bisthiacarbocyanine was qualitatively similar to a monomeric cyanine dye, but was more potent with 50% inhibition achieved at ~80 nM concentration. At all concentrations tested in aqueous solution, the bis-thiacarbocyanine collapsed to form a closed clamshell structure. However, the presence of tau protein selectively stabilized the open conformation. These results suggest that the inhibitory activity of bis-thiacarbocyanine results from multivalency, and reveal a route to more potent tau aggregation inhibitors.

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Anionic Micelles and Vesicles Induce Tau Fibrillization in Vitro

Cited by 220 publications

References 57 publications

Unsaturated Fatty Acids Induce Cytotoxic Aggregate Formation of Amyotrophic Lateral Sclerosis-linked Superoxide Dismutase 1 Mutants

Unsaturated Fatty Acids Induce Cytotoxic Aggregate Formation of Amyotrophic Lateral Sclerosis-linked Superoxide Dismutase 1 Mutants

Rapid Anionic Micelle-mediated α-Synuclein Fibrillization in Vitro

Potent inhibition of tau fibrillization with a multivalent ligand

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