Mitofusin-mediated ER stress triggers neurodegeneration in pink1/parkin models of Parkinson’s disease

Abstract

Mutations in PINK1 and PARKIN cause early-onset Parkinson's disease (PD), thought to be due to mitochondrial toxicity. Here, we show that in Drosophila pink1 and parkin mutants, defective mitochondria also give rise to endoplasmic reticulum (ER) stress signalling, specifically to the activation of the protein kinase R-like endoplasmic reticulum kinase (PERK) branch of the unfolded protein response (UPR). We show that enhanced ER stress signalling in pink1 and parkin mutants is mediated by mitofusin bridges, which occur between defective mitochondria and the ER. Reducing mitofusin contacts with the ER is neuroprotective, through suppression of PERK signalling, while mitochondrial dysfunction remains unchanged. Further, both genetic inhibition of dPerk-dependent ER stress signalling and pharmacological inhibition using the PERK inhibitor GSK2606414 were neuroprotective in both pink1 and parkin mutants. We conclude that activation of ER stress by defective mitochondria is neurotoxic in pink1 and parkin flies and that the reduction of this signalling is neuroprotective, independently of defective mitochondria. A video abstract for this article is available online in the supplementary information

Structure, function, and regulation of mitofusin‐2 in health and disease

“…Higher levels of Mfn2 in Parkin knockout mice fibroblasts and Parkinson's disease patients were responsible for increased ER-mitochondria association (Gautier et al, 2016). Similarly, drosophila PINK1/Parkin mutants displayed defective mitochondria and activated PERK-mediated UPR signalling (Celardo et al, 2016). Additionally, ER-mitochondria contact sites have been demonstrated as prime locations for Parkin-mediated autophagy, underscoring the importance of MAM as subcellular sites for autophagy induction (Yang & Yang, 2013).…”

From dysfunctional endoplasmic reticulum-mitochondria coupling to neurodegeneration

“…In contrast, we and others recently associated Parkin and PINK1 dysfunction with an exacerbation of the ER-mitochondria interface (Celardo et al, 2016;Gautier et al, 2016). In particular, ER-mitochondria juxtaposition was found to be increased in fibroblasts from patients with PARK2 or PARK6 mutations compared to cells from healthy donors (Celardo et al, 2016;Gautier et al, 2016). Similar structural alterations were observed in MEFs from PARK2 knock-out mice (Gautier et al, 2016) and brain tissue from pink1 and parkin flies (Celardo et al, 2016).…”

“…Parkin overexpression in nigral neurons also led to a slight increase in the percentage of mitochondria in contact with the ER (Zheng et al, 2017). In contrast, we and others recently associated Parkin and PINK1 dysfunction with an exacerbation of the ER-mitochondria interface (Celardo et al, 2016;Gautier et al, 2016). In particular, ER-mitochondria juxtaposition was found to be increased in fibroblasts from patients with PARK2 or PARK6 mutations compared to cells from healthy donors (Celardo et al, 2016;Gautier et al, 2016).…”

“…Approximately 10% of the cases are due to monogenic mutations . Physical and/or functional association with ER-mitochondria contacts was demonstrated in the case of the PD-related proteins α-synuclein (Cali et al, 2012;Guardia-Laguarta et al, 2014), DJ-1 , PINK1 (Celardo et al, 2016;Gelmetti et al, 2017) and Parkin Celardo et al, 2016;Gautier et al, 2016;Gelmetti et al, 2017;Van Laar et al, 2015;Zheng et al, 2017).…”

“…Thus, Mfn2 silencing restored defects in models with either decreased or increased ER-mitochondria coupling (Area- Celardo et al, 2016;Gautier et al, 2016). We will discuss possible explanations for these recurrent controversies in section 5.…”