Abstract
The accumulation of α-synuclein (αSyn) has been implicated as a causal factor in the pathogenesis of Parkinson’s disease (PD). There is growing evidence that supports mitochondrial dysfunction as a potential primary cause of dopaminergic neuronal death in PD. Here, we focused on reciprocal interactions between αSyn aggregation and mitochondrial injury induced by oxidative stress. We further investigated whether epidermal fatty acid-binding protein 5 (FABP5) is related to αSyn oligomerization/aggregation and subsequent disturbances in mitochondrial function in neuronal cells. In the presence of rotenone, a mitochondrial respiratory chain complex I inhibitor, co-overexpression of FABP5 with αSyn significantly decreased the viability of Neuro-2A cells compared to that of αSyn alone. Under these conditions, FABP5 co-localized with αSyn in the mitochondria, thereby reducing mitochondrial membrane potential. Furthermore, we confirmed that pharmacological inhibition of FABP5 by its ligand prevented αSyn accumulation in mitochondria, which led to cell death rescue. These results suggested that FABP5 is crucial for mitochondrial dysfunction related to αSyn oligomerization/aggregation in the mitochondria induced by oxidative stress in neurons.
Highlights
Parkinson’s disease (PD) is the second-most common neurodegenerative disease, and is caused by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) [1]
This effect of rotenone was evident when treated at a moderate concentration (0.5 μM), which failed to decrease cell survival in αSyn-transfected cells. These results suggested that fatty acid-binding protein 5 (FABP5) enhances oxidative stress toxicity in the presence of αSyn
We demonstrated that FABP5 plays a key role in oligomerization and aggregation of αSyn under oxidative stress in Neuro-2A cells
Summary
Parkinson’s disease (PD) is the second-most common neurodegenerative disease, and is caused by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) [1]. The neuropathological hallmark of PD is the accumulation of intracellular protein inclusions composed primarily of α-synuclein (αSyn), which are termed Lewy bodies [2,3]. ΑSyn aggregation has been widely reported to be a harbinger of subsequent pathology that leads to neurodegeneration [4]. ΑSyn is expressed presynaptically as a native unfolded protein that can form oligomers, protofibrils, or amyloid fibrils [5,6]. Among the different species of αSyn, pre-fibrillar oligomers are considered to be toxic to neurons [7]. The development of treatments aimed at reducing αSyn synthesis, secretion, aggregation, and increasing the clearance of pathogenic formations has become the most promising means to overcome Parkinson’s disease [8,9]. Several lines of evidence support mitochondrial dysfunction as a primary pathogenic mechanism in PD. The most convincing evidence first appeared from accidental human exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydrodropyridine, a metabolite that induces
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