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?-Synuclein suppresses both the initiation and amplification steps of ?-synuclein aggregation via competitive binding to surfaces.

ABSTRACT: ?-Synuclein is an intrinsically disordered protein that is associated with the pathogenesis of Parkinson's disease through the processes involved in the formation of amyloid fibrils. ? and ?-synuclein are homologous proteins found at comparable levels in presynaptic terminals but ?-synuclein has a greatly reduced propensity to aggregate and indeed has been found to inhibit ?-synuclein aggregation. In this paper, we describe how sequence differences between ?- and ?-synuclein affect individual microscopic processes in amyloid formation. In particular, we show that ?-synuclein strongly suppresses both lipid-induced aggregation and secondary nucleation of ?-synuclein by competing for binding sites at the surfaces of lipid vesicles and fibrils, respectively. These results suggest that ?-synuclein can act as a natural inhibitor of ?-synuclein aggregation by reducing both the initiation of its self-assembly and the proliferation of its aggregates.

SUBMITTER: Brown JW

PROVIDER: S-EPMC5093550 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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β-Synuclein suppresses both the initiation and amplification steps of α-synuclein aggregation via competitive binding to surfaces.

Brown James W P JW Buell Alexander K AK Michaels Thomas C T TC Meisl Georg G Carozza Jacqueline J Flagmeier Patrick P Vendruscolo Michele M Knowles Tuomas P J TP Dobson Christopher M CM Galvagnion Céline C

Scientific reports 20161103

α-Synuclein is an intrinsically disordered protein that is associated with the pathogenesis of Parkinson's disease through the processes involved in the formation of amyloid fibrils. α and β-synuclein are homologous proteins found at comparable levels in presynaptic terminals but β-synuclein has a greatly reduced propensity to aggregate and indeed has been found to inhibit α-synuclein aggregation. In this paper, we describe how sequence differences between α- and β-synuclein affect individual mi ...[more]

PMID: 27808107

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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

?-Synuclein suppresses both the initiation and amplification steps of ?-synuclein aggregation via competitive binding to surfaces.

Publications

β-Synuclein suppresses both the initiation and amplification steps of α-synuclein aggregation via competitive binding to surfaces.

Similar Datasets

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