|ZFIN ID: ZDB-PUB-190925-8|
Restriction of mitochondrial calcium overload by mcu inactivation renders neuroprotective effect in Zebrafish models of Parkinson's disease
Soman, S.K., Bazała, M., Keatinge, M., Bandmann, O., Kuznicki, J.
|Source:||Biology Open 8(10): (Journal)|
|Registered Authors:||Bandmann, Oliver, Keatinge, Marcus, Kuznicki, Jacek|
|Keywords:||CRISPR/Cas9, Mitochondria, Neuroprotection, Parkinson's disease, Zebrafish, mcu|
|PubMed:||31548178 Full text @ Biol. Open|
Soman, S.K., Bazała, M., Keatinge, M., Bandmann, O., Kuznicki, J. (2019) Restriction of mitochondrial calcium overload by mcu inactivation renders neuroprotective effect in Zebrafish models of Parkinson's disease. Biology Open. 8(10):.
ABSTRACTThe loss of dopaminergic neurons (DA) is a pathological hallmark of sporadic and familial forms of Parkinson's Disease (PD). We had previously shown that inhibiting mitochondrial calcium uniporter (mcu) using morpholinos can rescue DA neurons in pink1-/- zebrafish model of PD. In this study, we are showing results from our studies in mcu knockout zebrafish, which was generated using the CRISPR/Cas9 system. Functional assays confirmed impaired mitochondrial calcium influx in mcu-/- zebrafish. We also used in-vivo calcium imaging and fluorescent assays in purified mitochondria to investigate mitochondrial calcium dynamics in a pink1-/- zebrafish model of PD. Mitochondrial morphology was evaluated in DA neurons and muscle fibres using immunolabelling and transgenic lines, respectively. We observed diminished mitochondrial volume in DA neurons of pink1-/- zebrafish, while deletion of mcu restored mitochondrial volume. In contrast, the mitochondrial volume in muscle fibers was not restored after inactivation of mcu in pink1-/- zebrafish. Mitochondrial calcium overload coupled with depolarization of mitochondrial membrane potential leads to mitochondrial dysfunction in pink1-/- zebrafish model of PD. We used in situ hybridisation and immunohistochemical labelling of DA neurons to evaluate the effect of mcu deletion on DA neuronal clusters in the ventral telencephalon of zebrafish brain. We show that DA neurons are rescued after deletion of mcu in pink1-/- and the MPTP zebrafish model of PD. Thus, inactivation of mcu is protective in both genetic and chemical models of PD. Our data reveal that regulating mcu function could be an effective therapeutic target in PD pathology.