Melatonin rescues zebrafish embryos from the parkinsonian phenotype restoring the parkin/PINK1/DJ‐1/MUL1 network

Abstract

Multiple studies reporting mitochondrial impairment in Parkinson's disease (PD) involve knockout or knockdown models to inhibit the expression of mitochondrial-related genes, including parkin, PINK1, and DJ-1 ones. Melatonin has significant neuroprotective properties, which have been related to its ability to boost mitochondrial bioenergetics. The meaning and molecular targets of melatonin in PD are yet unclear. Zebrafish are an outstanding model of PD because they are vertebrates, their dopaminergic system is comparable to the nigrostriatal system of humans, and their brains express the same genes as mammals. The exposure of 24 hpf zebrafish embryos to MPTP leads to a significant inhibition of the mitochondrial complex I and the induction of sncga gene, responsible for enhancing γ-synuclein accumulation, which is related to mitochondrial dysfunction. Moreover, MPTP inhibited the parkin/PINK1/DJ-1 expression, impeding the normal function of the parkin/PINK1/DJ-1/MUL1 network to remove the damaged mitochondria. This situation remains over time, and removing MPTP from the treatment did not stop the neurodegenerative process. On the contrary, mitochondria become worse during the next 2 days without MPTP, and the embryos developed a severe motor impairment that cannot be rescued because the mitochondrial-related gene expression remained inhibited. Melatonin, added together with MPTP or added once MPTP was removed, prevented and recovered, respectively, the parkinsonian phenotype once it was established, restoring gene expression and normal function of the parkin/PINK1/DJ-1/MUL1 loop and also the normal motor activity of the embryos. The results show, for the first time, that melatonin restores brain function in zebrafish suffering with Parkinson-like disease.

Salidroside Protects against MPP+‐Induced Neuronal Injury through DJ‐1‐Nrf2 Antioxidant Pathway

“…Recent evidence has also suggested that abnormal function of DJ-1 plays a role in the pathogenesis of PD [42–44]. In this study, we also examined the role of DJ-1 in neuroprotective effects of Sal.…”

Oral Mucositis: Melatonin Gel an Effective New Treatment

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“…The administration of MPTP/MPP + also leads to a reduction in the mRNA and expression of fibroblast growth factor 9 (FGF9), which participates in the proliferation, differentiation, and survival of the cell. The expression and function of parkin/PINK1/DJ-1/MUL1 loop, which plays an important role in maintaining mitochondrial homeostasis, are also altered by this toxin [150, 158]. All these changes were normalized by melatonin treatment [148, 150, 154, 158] (Table 2).…”