Abstract
The association of α-synuclein (α-syn) with mitochondria occurs through interaction with mitochondrial complex I. Defects in this protein have been linked to the pathogenesis of Parkinson disease (PD). Overexpression of α-synuclein in cells has been suggested to cause elevations in mitochondrial oxidant radicals and structural and functional abnormalities in mitochondria. Asiatic acid (AA), a triterpenoid, is an antioxidant that is used for depression, and we have shown that pretreatment with AA can prevent PD-like damage, but its therapeutic effects in PD and mechanism remain unknown. In this study, we found that 0.5–2 mg AA/100 g diet significantly improves climbing ability in drosophila and extends their life-span—effects that we attributed to its antioxidant properties. AA also protected mitochondria against oxidative stress and apoptosis in a rotenone-induced cellular model. In an isolated mitochondria model, AA attenuated the decline in mitochondrial membrane potential that was induced by α-syn. Consequently, AA maintained membrane integrity and ATP production. Finally, we demonstrated that AA protects by blocking the translocation of α-syn into mitochondria. Our results suggest that mitochondria are crucial in PD and that AA is an excellent candidate for the prevention and therapy of this disease.
Highlights
Parkinson disease (PD) is a progressive neurodegenerative disorder that is characterized by the preferential loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc)(Moore et al, 2005) and the formation of intracytoplasmic protein aggregates, termed Lewy bodies, a major component of which is α-synuclein (α-syn) (Spillantini et al, 1997)
We found that Asiatic acid (AA) protects against Parkinsonlike injury in drosophila, SH-SY5Y cells, and isolated mitochondria
Many observations suggest that α-syn causes neurodegeneration by interfering with multiple signaling pathways. α-syn protein can form plasma membrane channels or modify their activity, altering membrane permeability to ions; abnormally associate with mitochondria and cause mitochondrial dysfunction; and interfere with autophagy regulation (Ottolini et al, 2017)
Summary
Parkinson disease (PD) is a progressive neurodegenerative disorder that is characterized by the preferential loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc)(Moore et al, 2005) and the formation of intracytoplasmic protein aggregates, termed Lewy bodies, a major component of which is α-synuclein (α-syn) (Spillantini et al, 1997). Increased expression of α-syn has been hypothesized to cause familial and sporadic PD, culminating in a loss of nigrostriatal dopaminergic neurons and motor deficits (Feany and Bender, 2000; Rochet et al, 2004; Lee and Trojanowski, 2006; Jellinger, 2012). In α-syn-expressing dopaminergic neuronal cultures, α-syn can translocate to the mitochondria, interact with respiratory complex I, and interfere with mitochondrial function (Devi et al, 2008). Recombinant human α-syn leads to a dose-dependent loss of mitochondrial transmembrane potential and phosphorylation capacity when incubated with isolated rat brain mitochondria (Banerjee et al, 2010). Hoogerheide et al (2017) found that α-syn molecules could be captured by a voltage-dependent anion channel (VDAC) using free energy considerations that allow α-synuclein translocation and retraction
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