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

ABSTRACT: The self-assembly of ?-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 ?-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 ?-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 ?-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 ?-synuclein, observing a dramatic reduction of ?-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.

SUBMITTER: Perni M

PROVIDER: S-EPMC5307473 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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

Perni Michele M Galvagnion Céline C Maltsev Alexander A Meisl Georg G Müller Martin B D MB Challa Pavan K PK Kirkegaard Julius B JB Flagmeier Patrick P Cohen Samuel I A SI Cascella Roberta R Chen Serene W SW Limbocker Ryan R Sormanni Pietro P Heller Gabriella T GT Aprile Francesco A FA Cremades Nunilo N Cecchi Cristina C Chiti Fabrizio F Nollen Ellen A A EA Knowles Tuomas P J TP Vendruscolo Michele M Bax Adriaan A Zasloff Michael M Dobson Christopher M CM

Proceedings of the National Academy of Sciences of the United States of America 20170117 6

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 b ...[more]

PMID: 28096355

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Project description:The two main pathological hallmarks of Parkinson's disease are loss of dopamine neurons in the substantia nigra pars compacta and proteinaceous amyloid fibrils composed mostly of ?-synuclein, called Lewy pathology. Levodopa to enhance dopaminergic transmission remains one of the most effective treatment for alleviating the motor symptoms of Parkinson's disease (Olanow, Mov Disord 34:812-815, 2019). In addition, deep brain stimulation (Bronstein et al., Arch Neurol 68:165, 2011) to modulate basal ganglia circuit activity successfully alleviates some motor symptoms. MRI guided focused ultrasound in the subthalamic nucleus is a promising therapeutic strategy as well (Martinez-Fernandez et al., Lancet Neurol 17:54-63, 2018). However, to date, there exists no treatment that stops the progression of this disease. The findings that ?-synuclein can be released from neurons and inherited through interconnected neural networks opened the door for discovering novel treatment strategies to prevent the formation and spread of Lewy pathology with the goal of halting PD in its tracks. This hypothesis is based on discoveries that pathologic aggregates of ?-synuclein induce the endogenous ?-synuclein protein to adopt a similar pathologic conformation, and is thus self-propagating. Phase I clinical trials are currently ongoing to test treatments such as immunotherapy to prevent the neuron to neuron spread of extracellular aggregates. Although tremendous progress has been made in understanding how Lewy pathology forms and spreads throughout the brain, cell intrinsic factors also play a critical role in the formation of pathologic ?-synuclein, such as mechanisms that increase endogenous ?-synuclein levels, selective expression profiles in distinct neuron subtypes, mutations and altered function of proteins involved in ?-synuclein synthesis and degradation, and oxidative stress. Strategies that prevent the formation of pathologic ?-synuclein should consider extracellular release and propagation, as well as neuron intrinsic mechanisms.

Dataset Information

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

Publications

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

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