Session Information
Date: Tuesday, June 21, 2016
Session Title: Parkinson's disease: Genetics
Session Time: 12:30pm-2:00pm
Location: Exhibit Hall located in Hall B, Level 2
Objective: To further elucidate the interaction between mitochondrial calcium homeostasis and PINK1 deficiency in a zebrafish (Danio rerio) model of Parkinson’s disease (PD).
Background: Loss of PINK1 function causes dysregulation of mitochondrial calcium homeostasis, resulting in mitochondrial dysfunction and neuronal cell death. The voltage-dependent anion channel 1 (VDAC1) is located within the outer mitochondrial membrane and transports calcium into the intermembrane space. Calcium then enters the mitochondrial matrix through a dedicated channel within the inner mitochondrial membrane referred to as the mitochondrial calcium uniporter (MCU). The aim of our study was to further determine the interaction between calcium homeostasis and survival of dopaminergic neurons in pink1-/- zebrafish.
Methods: Both MCU and VDAC1 were inactivated genetically, using morpholino antisense strategy. In addition, MCU was also inactivated pharmacologically. The effect of either MCU or VDAC1 inhibition on the survival of dopaminergic neurons and complex I activity of the mitochondrial respiratory chain were assessed using whole mount in situ hybridisation (WISH) for tyrosine hydroxylase (TH) and spectrophotometric methods respectively. Gene expression levels of MCU regulators were quantified using Q-PCR.
Results: Both genetic and pharmacological inactivation of MCU prevented dopaminergic neuronal cell loss in pink-/- zebrafish larvae via rescue of complex I activity. In contrast, genetic inactivation of VDAC1 did not rescue dopaminergic neurons. Subsequent gene expression studies revealed specific upregulation of the MCU regulator MICU1 in pink-/- zebrafish larvae. Inactivation of MICU1 also results in rescue of dopaminergic neurons.
Conclusions: Our data suggest modulation of MCU-mediated mitochondrial calcium homeostasis as a possible neuroprotective strategy in PINK1 mutant PD.
To cite this abstract in AMA style:
B. Oliver, S. Solman, M. Keatinge, M. DaCosta, H. Mortiboys, S. Sugunan, J. Kuznicki. Inhibition of the mitochondrial calcium uniporter (MCU) rescues dopaminergic neurons in pink1-/- zebrafish [abstract]. Mov Disord. 2016; 31 (suppl 2). https://www.mdsabstracts.org/abstract/inhibition-of-the-mitochondrial-calcium-uniporter-mcu-rescues-dopaminergic-neurons-in-pink1-zebrafish/. Accessed May 14, 2025.« Back to 2016 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/inhibition-of-the-mitochondrial-calcium-uniporter-mcu-rescues-dopaminergic-neurons-in-pink1-zebrafish/