Aminochrome has been reported to induce lysosomal dysfunction by inhibiting the vacuolar H-type ATPase localized in lysosome membrane. DT-diaphorase has been proposed to prevent aminochrome neurotoxicity but it is unknown whether this enzyme prevents aminochrome-induced lysosomal dysfunction. In the present study, we tested the protective role of DT-diaphorase in lysosomal dysfunction by generating a cell line (SH-SY5YsiNQ7) with a stable expression of a siRNA against DT-diaphorase with only 10% expression of mRNA enzyme. The cells differentiated with retinoic acid and 12-o-tetradecanoylphorbol-13-acetate show a significant increase in the expression of tyrosine hydroxylase, vesicular monoamine transporter-2, and dopamine transporter. The incubation of SH-SY5YsiNQ7 cells with 10 μM aminochrome resulted in a significant decrease of lysosome pH determined by using acridine orange, while aminochrome has no effect on SH-SY5Y cells. These results support the proposed protective role of DT-diaphorase against aminochrome-induced lysosomal dysfunction.
Four decades after L-dopa was introduced as a therapy for Parkinson's disease, it is still the gold standard for Parkinson's pharmacological treatment because no new drug has been discovered. This is due to the ambiguity regarding the molecular mechanisms responsible for the degeneration of dopaminergic neurons containing neuromelanin in the substantia nigra, which induces the motor symptoms of Parkinson's disease. The question is to identify the mechanisms underlying the neurodegenerative process of Parkinson's disease initiated years before the motor symptoms are evident, through pre-motor symptoms. The possible role of an exogenous environmental neurotoxin has been proposed. However, MPTP generates severe Parkinsonism in just 3 days, in contrast with idiopathic Parkinson's disease, which occurs after years of slow degeneration. The discovery of proteins (such as alpha synuclein and parkin) associated with the familial form of the disease opened new lines of basic research, resulting in a general agreement that five mechanisms are involved in the degeneration of dopaminergic neurons containing neuromelanin: protein degradation dysfunction, mitochondrial dysfunction, alpha synuclein aggregation, oxidative stress and neuroinflammation. Dopamine oxidation sequentially generates dopamine o-quinone, aminochrome, 5,6-indolequinone and finally, neuromelanin. These o-quinones have been reported to be directly involved in four of
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