The Anti-Parkinsonian Drug Selegiline Delays the Nucleation Phase of α-Synuclein Aggregation Leading to the Formation of Nontoxic Species

Braga, Carolina A.; Follmer, Cristian; Palhano, Fernando L.; Khattar, Elias; Freitas, Mônica S.; Romão, Luciana; Giovanni, Saviana Di; Lashuel, Hilal A.; Silva, Jerson L.; Foguel, Débora

doi:10.1016/j.jmb.2010.10.027

Cited by 83 publications

(54 citation statements)

References 74 publications

(100 reference statements)

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“…44 The SH-SY5Y cells were differentiated using retinoic acid for 5 days (Supporting Information Figure S2a) and subsequently treated with α-Syn oligomers in the presence and absence of curcumin, and only buffer was used as a control. After 40 h of incubation, the attached cells in each culture dish were fixed and immunostained with synaptophysin ( Figure 1e).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Curcumin Modulates α-Synuclein Aggregation and Toxicity

Singh

Kotia

Ghosh

et al. 2012

ACS Chem. Neurosci.

264

242

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In human beings, Parkinson's disease (PD) is associated with the oligomerization and amyloid formation of α-synuclein (α-Syn). The polyphenolic Asian food ingredient curcumin has proven to be effective against a wide range of human diseases including cancers and neurological disorders. While curcumin has been shown to significantly reduce cell toxicity of α-Syn aggregates, its mechanism of action remains unexplored. Here, using a series of biophysical techniques, we demonstrate that curcumin reduces toxicity by binding to preformed oligomers and fibrils and altering their hydrophobic surface exposure. Further, our fluorescence and two-dimensional nuclear magnetic resonance (2D-NMR) data indicate that curcumin does not bind to monomeric α-Syn but binds specifically to oligomeric intermediates. The degree of curcumin binding correlates with the extent of α-Syn oligomerization, suggesting that the ordered structure of protein is required for effective curcumin binding. The acceleration of aggregation by curcumin may decrease the population of toxic oligomeric intermediates of α-Syn. Collectively; our results suggest that curcumin and related polyphenolic compounds can be pursued as candidate drug targets for treatment of PD and other neurological diseases.

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Section: ■ Results and Discussionmentioning

confidence: 99%

“…The data indicate the unstructured state of the protein. We used published 1 H and 15 N chemical shift values 44,64 for assigning those spectra. The spectra of α-Syn .…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Curcumin Modulates α-Synuclein Aggregation and Toxicity

Singh

Kotia

Ghosh

et al. 2012

ACS Chem. Neurosci.

264

242

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“…Several studies have focused recently on the role of small molecules that interact with AS and inhibit its aggregation-fibrillation in vitro and in vivo (19,20,23,(25)(26)(27)(28)(29). Polyphenols, flavonoids, porphyrins, and phthalocyanines are all polyaromatic scaffolds included in this group of compounds.…”

Section: Discussionmentioning

confidence: 99%

Toward the Discovery of Effective Polycyclic Inhibitors of α-Synuclein Amyloid Assembly

Lamberto

Torres-Monserrat

Bertoncini

et al. 2011

Journal of Biological Chemistry

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The fibrillation of amyloidogenic proteins is a critical step in the etiology of neurodegenerative disorders such as Alzheimer and Parkinson diseases. There is major interest in the therapeutic intervention on such aberrant aggregation phenomena, and the utilization of polyaromatic scaffolds has lately received considerable attention. In this regard, the molecular and structural basis of the anti-amyloidogenicity of polyaromatic compounds, required to evolve this molecular scaffold toward therapeutic drugs, is not known in detail. We present here biophysical and biochemical studies that have enabled us to characterize the interaction of metal-substituted, tetrasulfonated phthalocyanines ( The misfolding of proteins into a toxic conformation and their deposition as amyloid-like fibrils are proposed to be at the molecular foundation of a number of neurodegenerative disorders including Creutzfeldt-Jakob, Alzheimer, and Parkinson diseases (1-3). A detailed understanding of the mechanism by which proteins of wide structural diversity are transformed into morphologically similar aggregates is therefore of high clinical importance.␣-Synuclein (AS) 6 is a highly soluble, intrinsically disordered protein, expressed predominantly in the neurons of the central nervous system and localized at presynaptic terminals in close proximity to synaptic vesicles. Evidence that AS amyloidogenesis plays a causative role in the development of Parkinson diseases is furnished by a variety of genetic, neuropathological, and biochemical studies (4 -7). Structurally, AS comprises 140 amino acids distributed in three different regions: the amphipathic N terminus (residues 1-60), showing imperfect KTKEGV repeats and involved in lipid binding (8, 9); the highly hydrophobic self-aggregating sequence known as non-A␤ component (residues 61-95), presumed to initiate fibrillation (10); and the acidic C-terminal region (residues 96 -140), rich in Pro, Asp, and Glu residues and critical for blocking rapid AS filament assembly (11,12). In its native monomeric state AS is best described as an ensemble of structurally heterogeneous conformations, with no persistent secondary structure and with long range interresidue interactions that have been shown to stabilize aggregation-autoinhibited conformations (13-15). However, the mechanism(s) underlying the structural transition from the innocuous, monomeric AS to its neurotoxic form still remain poorly described.The use of aggregation inhibitors as molecular probes of the structural and toxic mechanisms related to amyloid formation * This work was supported by the Agencia Nacional de Promoció n Científica y Tecnoló gica, Argentina, Fundacíon Antorchas, Max Planck Society, Alexander von Humboldt Foundation, Fundació n Josefina Prats, and the Government of Santa Fe. The Bruker Avance II 600 MHz NMR spectrometer used in this work was purchased with funds from ANPCyT (PME2003-2006

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“…The sample for structure determination contained 0.65 mM CDNF in 20 mM sodium phosphate, pH 6, 100 mM NaCl, 3 mM NaN 3 , 1 mM EDTA, and 10% (v/v) D 2 O. The oligomers of recombinant ␣-synuclein were produced as described previously (23).…”

Section: Methodsmentioning

confidence: 99%

The Solution Structure and Dynamics of Full-length Human Cerebral Dopamine Neurotrophic Factor and Its Neuroprotective Role against α-Synuclein Oligomers

Latge

Cabral

Oliveira

et al. 2015

Journal of Biological Chemistry

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Background: Cerebral dopamine neurotrophic factor (CDNF) is a promising therapeutic agent for treating Parkinson disease. Results: We determined the solution structure of CDNF and demonstrated its neuroprotective effects against insults caused by ␣-synuclein oligomers. Conclusion:We identified structural features of CDNF that might correspond with its physiological activity. Significance: This work strengthens the therapeutic relevance of using CDNF to treat neurodegenerative diseases.

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The Anti-Parkinsonian Drug Selegiline Delays the Nucleation Phase of α-Synuclein Aggregation Leading to the Formation of Nontoxic Species

Cited by 83 publications

References 74 publications

Curcumin Modulates α-Synuclein Aggregation and Toxicity

Curcumin Modulates α-Synuclein Aggregation and Toxicity

Toward the Discovery of Effective Polycyclic Inhibitors of α-Synuclein Amyloid Assembly

The Solution Structure and Dynamics of Full-length Human Cerebral Dopamine Neurotrophic Factor and Its Neuroprotective Role against α-Synuclein Oligomers

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