Objective: To determine whether PINK1 deficiency impairs adult neurogenesis in a tractable vertebrate model of PINK1-related Parkinson’s disease (PD).

Background: PD is characterized by loss of dopaminergic (DA) neurons in the substantia nigra. PD-genes, including PINK1, may regulate neurogenesis, however it is unknown whether DA neurogenesis is altered in PD. Zebrafish are a widely used vertebrate model to study neurogenesis through development and in adulthood. We previously characterised a pink1 stable mutant zebrafish line (pink-/-) [1,2]. The aim of this study was to determine whether zebrafish DA neurons are generated throughout life and to elucidate whether PINK1-deficiency results in impaired neurogenesis.


Methods: DA neuronal populations within the zebrafish posterior tuberculum (PT), homologous to the substantia nigra, were classified as previously described. EdU pulse-chase analyses, in combination with tyrosine hydroxylase-1 antibody labelling, was used to identify newborn DA neurons in the adult wild type PT (3-, 6-, 12- and 22-months of age) and in pink1-/- PT (3-months of age). EdU+;Th1+ neurons were quantitated in DA neuron subpopulations in pink1+/+ and pink1-/- brain sections in 3-month-old zebrafish.

Results: DA neurons are newly generated in the periventricular nucleus (TPp) and the paraventricular organ (PVO) at adult stages (3-, 6- and 12-months), at a rate that decreases with age. TPp and PVO DA neurogenesis at later stages (22-months) is reduced, where no newborn DA neurons were observed in any subpopulation. PINK1-deficiency does not alter overall levels of proliferation, but results in a reduced population of OTP+ progenitors in the TPp (p=0.0259) and impeded DA neurogenesis in both the TPp (p=0.0078) and the PVO (p=0.0017).

Conclusions: Together, our findings show for the first time that both ascending and locally projecting dopamine neurons are added to in adult life in zebrafish, and that this generation is restricted to early adulthood. Our observations of impeded adult neurogenesis in PINK1-deficient zebrafish suggests the possible relevance of impaired neurogenesis, including early adult neurogenesis, in PINK1-related PD, which may contribute to disease onset or progression.

References: 1. Flinn LJ, Keatinge K, Bretaud S, et al (2013): TigarB causes mitochondrial dysfunction and neuronal loss in PINK1 deficiency. Ann Neurol 74:837-847. 2. Soman S, Keatinge M, Moein M, et al (2017): Inhibition of the mitochondrial calcium uniporter rescues dopaminergic neurons in pink1-/- zebrafish. Eur J Neurosci 45:528-535.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/adult-neurogenesis-is-impaired-in-pink1-zebrafish-danio-rerio/