A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity

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Significance

Parkinson’s disease is characterized by the presence in brain tissues of aberrant aggregates primarily formed by the protein α-synuclein. It has been difficult, however, to identify compounds capable of preventing the formation of such deposits because of the complexity of the aggregation process of α-synuclein. By exploiting recently developed highly quantitative in vitro assays, we identify a compound, squalamine, that blocks α-synuclein aggregation, and characterize its mode of action. Our results show that squalamine, by competing with α-synuclein for binding lipid membranes, specifically inhibits the initiation of the aggregation process of α-synuclein and abolishes the toxicity of α-synuclein oligomers in neuronal cells and in an animal model of Parkinson’s disease.

Abstract

The self-assembly of α-synuclein is closely associated with Parkinson’s disease and related syndromes. We show that squalamine, a natural product with known anticancer and antiviral activity, dramatically affects α-synuclein aggregation in vitro and in vivo. We elucidate the mechanism of action of squalamine by investigating its interaction with lipid vesicles, which are known to stimulate nucleation, and find that this compound displaces α-synuclein from the surfaces of such vesicles, thereby blocking the first steps in its aggregation process. We also show that squalamine almost completely suppresses the toxicity of α-synuclein oligomers in human neuroblastoma cells by inhibiting their interactions with lipid membranes. We further examine the effects of squalamine in a Caenorhabditis elegans strain overexpressing α-synuclein, observing a dramatic reduction of α-synuclein aggregation and an almost complete elimination of muscle paralysis. These findings suggest that squalamine could be a means of therapeutic intervention in Parkinson’s disease and related conditions.

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Most cited references 31

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C. elegans: des neurones et des gènes

Jean-Louis Bessereau, Christelle Gally (2003)

The human brain contains 100 billion neurons and probably one thousand times more synapses. Such a system can be analyzed at different complexity levels, from cognitive functions to molecular structure of ion channels. However, it remains extremely difficult to establish links between these different levels. An alternative strategy relies on the use of much simpler animals that can be easily manipulated. In 1974, S. Brenner introduced the nematode Caenorhabditis elegans as a model system. This worm has a simple nervous system that only contains 302 neurons and about 7,000 synapses. Forward genetic screens are powerful tools to identify genes required for specific neuron functions and behaviors. Moreover, studies of mutant phenotypes can identify the function of a protein in the nervous system. The data that have been obtained in C. elegans demonstrate a fascinating conservation of the molecular and cellular biology of the neuron between worms and mammals through more than 550 million years of evolution.

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Membrane phosphatidylserine regulates surface charge and protein localization.

Tony Yeung, Gary E Gilbert, Jialan Shi … (2008)

Electrostatic interactions with negatively charged membranes contribute to the subcellular targeting of proteins with polybasic clusters or cationic domains. Although the anionic phospholipid phosphatidylserine is comparatively abundant, its contribution to the surface charge of individual cellular membranes is unknown, partly because of the lack of reagents to analyze its distribution in intact cells. We developed a biosensor to study the subcellular distribution of phosphatidylserine and found that it binds the cytosolic leaflets of the plasma membrane, as well as endosomes and lysosomes. The negative charge associated with the presence of phosphatidylserine directed proteins with moderately positive charge to the endocytic pathway. More strongly cationic proteins, normally associated with the plasma membrane, relocalized to endocytic compartments when the plasma membrane surface charge decreased on calcium influx.

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Molecular pathways of neurodegeneration in Parkinson's disease.

Ted Dawson, Valina Dawson (2003)

Parkinson's disease (PD) is a complex disorder with many different causes, yet they may intersect in common pathways, raising the possibility that neuroprotective agents may have broad applicability in the treatment of PD. Current evidence suggests that mitochondrial complex I inhibition may be the central cause of sporadic PD and that derangements in complex I cause alpha-synuclein aggregation, which contributes to the demise of dopamine neurons. Accumulation and aggregation of alpha-synuclein may further contribute to the death of dopamine neurons through impairments in protein handling and detoxification. Dysfunction of parkin (a ubiquitin E3 ligase) and DJ-1 could contribute to these deficits. Strategies aimed at restoring complex I activity, reducing oxidative stress and alpha-synuclein aggregation, and enhancing protein degradation may hold particular promise as powerful neuroprotective agents in the treatment of PD.

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Author and article information

Journal

Journal ID (nlm-ta): Proc Natl Acad Sci U S A

Journal ID (iso-abbrev): Proc. Natl. Acad. Sci. U.S.A

Journal ID (hwp): pnas

Journal ID (pmc): pnas

Journal ID (publisher-id): PNAS

Title: Proceedings of the National Academy of Sciences of the United States of America

Publisher: National Academy of Sciences

ISSN (Print): 0027-8424

ISSN (Electronic): 1091-6490

Publication date (Print): 7 February 2017

Publication date (Electronic): 17 January 2017

Publication date PMC-release: 17 January 2017

Volume: 114

Issue: 6

Pages: E1009-E1017

Affiliations

[1] ^aDepartment of Chemistry, University of Cambridge , Cambridge CB2 1EW, United Kingdom;

[2] ^bUniversity Medical Centre Groningen, European Research Institute for the Biology of Aging, University of Groningen, Groningen 9713 AV, The Netherlands;

[3] ^cLaboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, MD 20892;

[4] ^dDepartment of Applied Mathematics and Theoretical Physics, University of Cambridge , Cambridge CB3 0WA, United Kingdom;

[5] ^eDepartment of Experimental and Clinical Biomedical Sciences, University of Florence , Florence 50134, Italy;

[6] ^fBiocomputation and Complex Systems Physics Institute (BIFI)-Joint Unit BIFI-IQFR (CSIC), University of Zaragoza , 50018 Zaragoza, Spain;

[7] ^gMedStar–Georgetown Transplant Institute, Georgetown University School of Medicine , Washington, DC 20010

Author notes

²To whom correspondence may be addressed. Email: mv245@ 123456cam.ac.uk , bax@ 123456nih.gov , maz5@ 123456georgetown.edu , or cmd44@ 123456cam.ac.uk .

Edited by Gregory A. Petsko, Weill Cornell Medical College, New York, NY, and approved December 5, 2016 (received for review June 29, 2016)

Author contributions: M.P., E.A.A.N., T.P.J.K., M.V., A.B., M.Z., and C.M.D. designed research; M.P., C.G., A.M., G.M., M.B.D.M., P.K.C., J.B.K., P.F., R.C., R.L., P.S., G.T.H., F.A.A., C.C., F.C., T.P.J.K., A.B., and M.Z. performed research; P.K.C., S.W.C., N.C., and E.A.A.N. contributed new reagents/analytic tools; M.P., C.G., A.M., G.M., P.K.C., J.B.K., P.F., S.I.A.C., R.C., R.L., P.S., C.C., F.C., E.A.A.N., T.P.J.K., A.B., M.Z., and C.M.D. analyzed data; and M.P., T.P.J.K., M.V., A.B., M.Z., and C.M.D. wrote the paper.

¹Present address: German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany, and Institute of Physical Biology, Heinrich Heine Universität, Universitätsstr.1, 40225 Duesseldorf, Germany.