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 c-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 mitochondrialrelated
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