Loss of PINK1 enhances neurodegeneration in a mouse model of Parkinson's disease triggered by mitochondrial stress

Abstract

Parkinson's disease (PD) shows a complex etiology, where both genetic and environmental factors contribute to initiation and advance of pathology. Mitochondrial dysfunction and mutation of genes implicated in mitochondria quality control are recognized contributors to etiopathology and progression of PD. Here we report the development and characterization of a genetic mouse model of PD with a combined etiology comprising: 1) induction of mitochondrial stress achieved through the expression of a mitochondrial matrix protein that accumulates in an unfolded state and 2) deletion of PINK1 gene. Using this model we address the role of PINK1 in mitochondrial quality control and disease progression.To induce mitochondrial stress specifically in catecholaminergic neurons we generated transgenic animals where the conditional expression of mitochondrial unfolded ornithine transcarbamylase (dOTC) is achieved under the tyrosine hydroxylase (Th) promoter. The mice were characterized in terms of survival, growth and motor behaviour. The characterization was followed by analysis of cell death induced in dopaminergic neurons and responsiveness to l-dopa. We demonstrate that accumulation of dOTC in dopaminergic neurons causes neurodegeneration and motor behaviour impairment that illustrates a parkinsonian phenotype. This associates with l-dopa responsiveness validating the model as a model of PD. The combined transgenic model where dOTC is overexpressed in PINK1 KO background presents increased neurodegeneration as compared to dOTC transgenic in wild-type background. Moreover, this combined model does not show responsiveness to l-dopa. Our in vivo data show that loss of PINK1 accelerates neurodegenerative phenotypes induced by mitochondrial stress triggered by the expression of an unfolded protein in this organelle.

Tissue- and Cell-Specific Mitochondrial Defect in Parkin-Deficient Mice

“…Therefore, as in cardiac tissue, the mitochondrial quality control function of the PINK1/Parkin pathway may become essential in the central nervous system under stress conditions, for example following accumulation of oxidative stress during ageing [63]. Consistent with this possibility, mitochondrial stress caused by the conditional expression of mitochondrial unfolded ornithine transcarbamylase has been recently shown to lead to dopaminergic neurodegeneration and a parkinsonian phenotype in PINK1−/− mice [64].…”

Systems genetics identifies Hp1bp3 as a novel modulator of cognitive aging

“…We found no differences between the Hp1bp3 KO and WT mice on these measures, suggesting that the effects of Hp1bp3 KO reported herein are not due to gross behavioral abnormalities. Other positional candidates identified in the CFM QTL, such as Pink1 and Kif17 (Table 1), have been linked to cognitive deficits (Roberson, et al, 2008) and neurodegeneration (Moisoi, et al, 2014) and contain variants that could impact gene function or expression. Here, we focused on genetic correlates of CFM expressed in the hippocampus due to the hippocampal-dependent nature of contextual fear conditioning (Chen, et al, 1996) and the fact that the hippocampus is one of the first structures affected in aging (Burke and Barnes, 2006; Gant, et al, 2006).…”

The Role of AMPK in Drosophila melanogaster

“…Pimenta de Castro and colleagues have speculated that AMPK-dependent autophagy may exert a protective role in this fly model of protein misfolding (2012). Notably, shortly after the Drosophila model of dOTC was published, researchers published a mouse model of PD where dOTC expression is driven by the tyrosine hydroxylase promoter (Moisoi et al 2014). This progression from early experiments in flies to ensuing studies in mice underscores the translational merit of Drosophila research.…”