Abstract
The aggregation of α-synuclein (α-syn) is considered the key pathogenic event in many neurological disorders such as Parkinson's disease (PD), dementia with Lewy bodies and multiple system atrophy, giving rise to a whole category of neurodegenerative diseases known as synucleinopathies. Although the molecular basis of α-syn toxicity has not been precisely elucidated, a great deal of effort has been put into identifying compounds that could inhibit or even reverse the aggregation process. Previous reports indicated that many phenolic compounds are potent inhibitors of α-syn aggregation. The aim of the present study was to assess the anti-aggregating effect of gallic acid (GA) (3,4,5-trihydroxybenzoic acid), a benzoic acid derivative that belongs to a group of phenolic compounds known as phenolic acids. By employing an array of biophysical and biochemical techniques and a cell-viability assay, GA was shown not only to inhibit α-syn fibrillation and toxicity but also to disaggregate preformed α-syn amyloid fibrils. Interestingly, GA was found to bind to soluble, non-toxic oligomers with no β-sheet content, and to stabilize their structure. The binding of GA to the oligomers may represent a potential mechanism of action. Additionally, by using structure activity relationship data obtained from fourteen structurally similar benzoic acid derivatives, it was determined that the inhibition of α-syn fibrillation by GA is related to the number of hydroxyl moieties and their position on the phenyl ring. GA may represent the starting point for designing new molecules that could be used for the treatment of PD and related disorders.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disorder, the incidence of which rises sharply after the fifth decade of life, affecting 1.4 and 3.4% of the population at 55 and 75 years of age, respectively (Wood, 1997)
Mitochondrial pathophysiology aggressively promotes neuronal dysfunction and loss of synaptic viability, leading to neurodegeneration (Perier and Vila, 2012), and accumulated evidence from both in vitro and in vivo studies, postulates a major pathogenic role for a α-syn in mitochondrial dysfunction, thereby providing a link between protein aggregation, mitochondrial damage, and neurodegeneration. These findings indicate a central role for α-syn aggregation in PD pathogenesis. α-Syn aggregation proceeds through several key intermediate stages, with monomeric α-syn first assembling into oligomeric forms that gradually generate insoluble amyloid fibrils
To assess whether gallic acid (GA) disaggregation of α-syn fibrils was accompanied by a decrease in α-syn toxicity, we evaluated the toxicity of the α-syn species that resulted from the disaggregation experiment on human neuroblastoma M17 cells (Figure 3D)
Summary
Parkinson’s disease (PD) is a neurodegenerative disorder, the incidence of which rises sharply after the fifth decade of life, affecting 1.4 and 3.4% of the population at 55 and 75 years of age, respectively (Wood, 1997). PD is characterized by the presence of intracellular inclusions known as Lewy bodies (LBs), the main constituent of which are α-synuclein (α-syn) fibrils (Spillantini et al, 1997; El-Agnaf et al, 1998). Accumulated results over the last few decades show that mitochondrial dysfunction followed by oxidative stress are both associated with neurodegenerative diseases (Leuner et al, 2007; Schmitt et al, 2012). Overexpression of α-syn, especially its mutant forms, is thought to enhance the Frontiers in Aging Neuroscience www.frontiersin.org
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