Dataset Information

Parkin Levels Decrease in Fibroblasts With Progranulin (PGRN) Pathogenic Variants and in a Cellular Model of PGRN Deficiency.

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.

SUBMITTER: Gaweda-Walerych K

PROVIDER: S-EPMC8155584 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Parkin Levels Decrease in Fibroblasts With Progranulin (PGRN) Pathogenic Variants and in a Cellular Model of PGRN Deficiency.

Gaweda-Walerych Katarzyna K Walerych Dawid D Berdyński Mariusz M Buratti Emanuele E Zekanowski Cezary C

Frontiers in molecular neuroscience 20210513

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 <i>PGRN</i> (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 ...[more]

PMID: 34054428

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Project description:Pendrin (SLC26A4) is an anion exchanger abundantly expressed in the inner ear, kidney and thyroid, and its malfunction resulting from genetic mutation leads to Pendred syndrome and non‑syndromic deafness DFNB4. Pathogenic variants of the pendrin protein are less expressed than the wild‑type, but the mechanism underlying this phenomenon is unknown. In the present study, the hypothesis that reduced protein expression stems from increased protein degradation was explored. To verify this hypothesis, the protein levels and anion transport function of several pathogenic pendrin variants were measured following exposure to inhibitors of the ubiquitin‑proteasome system (UPS) and the lysosomal/autophagosomal pathways. Protein levels were measured by western blotting and quantitative imaging; ion transport was measured with a fluorometric method. Post‑translational modification of pendrin was investigated by immunoprecipitation and mass spectrometry. The results showed that the protein abundance and half‑life of pathogenic pendrin variants were significantly reduced compared with the wild‑type in cell‑based assays and in a mouse model of Pendred syndrome/DFNB4, pointing to accelerated protein degradation rather than defective protein production. Wild‑type pendrin and its variants are abundantly but differentially ubiquitinated, consistent with their different protein stability. While ubiquitination at the C‑terminus controls the stability of wild‑type pendrin, preferential ubiquitination of lysine 77 occurred in the pathogenic pendrin variant p.R409H. Inhibition of the UPS with investigational (MG132) or clinical (bortezomib, delanzomib, or carfilzomib) proteasome inhibitors rescued the expression, plasma membrane targeting, and ion transport function of pathogenic pendrin variants, while inhibition of the lysosomal/autophagosomal pathway was ineffective. Among the compounds tested, carfilzomib rescued the ion transport of pendrin p.R409H to wild‑type levels. These findings suggest that targeting specific molecular players within the UPS can rescue the expression and activity of pathogenic variants of the pendrin protein, which represents a novel therapeutic concept for Pendred syndrome/DFNB4.

Dataset Information

Parkin Levels Decrease in Fibroblasts With Progranulin (PGRN) Pathogenic Variants and in a Cellular Model of PGRN Deficiency.

Publications

Parkin Levels Decrease in Fibroblasts With Progranulin (PGRN) Pathogenic Variants and in a Cellular Model of PGRN Deficiency.

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