Abstract
Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases with TDP-43 mislocalization and aggregation. Genetic forms of FTLD and ALS are caused by pathogenic variants in various genes, such as PGRN (progranulin). To date, depletion of parkin E3 ubiquitin protein ligase, a key mitophagy regulator, has been reported in sporadic ALS patients and ALS mice models with TDP-43 proteinopathy. In this work, we show parkin downregulation also in fibroblasts derived from FTLD patients with four different PGRN pathogenic variants. We corroborate this finding in control fibroblasts upon PGRN silencing, demonstrating additionally the decrease of parkin downstream targets, mitofusin 2 (MFN2) and voltage dependent anion channel 1 (VDAC1). Importantly, we show that TDP-43 overexpression rescues PRKN levels upon transient PGRN silencing, but not in FTLD fibroblasts with PGRN pathogenic variants, despite upregulating PGRN levels in both cases. Further observation of PRKN downregulation upon TDP-43 silencing, suggests that TDP-43 loss-of-function contributes to PRKN decrease. Our results provide further evidence that parkin downregulation might be a common and systemic phenomenon in neurodegenerative diseases with TDP- 43 loss-of-function.
Highlights
Mitochondrial dysfunction is one of the common mechanisms underlying the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) (Wang et al, 2013; Onesto et al, 2016; Davis et al, 2018)
Several seminal papers on mitophagy initiation have previously demonstrated that PINK1 (PTEN-induced kinase 1) recruits parkin to damaged mitochondria to prime selective mitophagy (Narendra et al, 2008, 2010; Matsuda et al, 2010), followed by PINK1/parkin— dependent ubiquitination of various mitochondrial outer membrane proteins, such as mitofusin 2 (MFN2) (Mitofusin 2), Tomm20, and voltage dependent anion channel 1 (VDAC1) (Glauser et al, 2011; Gaweda-Walerych and Zekanowski, 2013)
Since high glucose metabolism was shown to decrease parkin levels, which could be further exacerbated by PGRN deficiency (Zhou et al, 2019), we analyzed the effects of PGRN silencing both on glucose and galactose medium, obtaining similar results in both media (Figures 2A,B)
Summary
Mitochondrial dysfunction is one of the common mechanisms underlying the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) (Wang et al, 2013; Onesto et al, 2016; Davis et al, 2018). The main neuropathological hallmark of sporadic and genetic forms of ALS and FTLD caused by pathogenic variants in PGRN and many other genes, is TDP-43 (transactive response DNA-binding protein 43 kDa) pathology. It is characterized by TDP-43 protein depletion from the nucleus and its cytoplasmic accumulation as ubiquitin-positive inclusions (Neumann et al, 2006). This leads to both toxic gain- and loss-of-TDP-43 function, causing deregulation of various aspects. Regulation of parkin mRNA and protein levels, or its cellular localization has been linked to TDP-43 complex neuropathology or manipulations of TDP-43 expression, yielding discordant results (see Supplementary Table 3; Polymenidou et al, 2011; Lagier-Tourenne et al, 2012; Hebron et al, 2013; Davis et al, 2018; Sun et al, 2018)
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