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

Autor:	Gaweda-Walerych K; Laboratory of Neurogenetics, Mossakowski Medical Research Institute, Department of Neurodegenerative Disorders, Polish Academy of Sciences, Warsaw, Poland., Walerych D; Laboratory of Human Disease Multiomics, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland., Berdyński M; Laboratory of Neurogenetics, Mossakowski Medical Research Institute, Department of Neurodegenerative Disorders, Polish Academy of Sciences, Warsaw, Poland., Buratti E; Molecular Pathology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy., Zekanowski C; Laboratory of Neurogenetics, Mossakowski Medical Research Institute, Department of Neurodegenerative Disorders, Polish Academy of Sciences, Warsaw, Poland.
Jazyk:	angličtina
Zdroj:	Frontiers in molecular neuroscience [Front Mol Neurosci] 2021 May 13; Vol. 14, pp. 676478. Date of Electronic Publication: 2021 May 13 (Print Publication: 2021).
DOI:	10.3389/fnmol.2021.676478
Abstrakt:	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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Gaweda-Walerych, Walerych, Berdyński, Buratti and Zekanowski.)
Databáze:	MEDLINE
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