Cargando…

The Impact of ALS-Associated Genes hnRNPA1, MATR3, VCP and UBQLN2 on the Severity of TDP-43 Aggregation

Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder, characterized by cytoplasmic inclusions of RNA-binding protein TDP-43. Despite decades of research and identification of more than 50 genes associated with amyotrophic lateral sclerosis (ALS), the cause of TDP-43 translocatio...

Descripción completa

Detalles Bibliográficos
Autores principales: Bajc Česnik, Ana, Motaln, Helena, Rogelj, Boris
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465640/
https://www.ncbi.nlm.nih.gov/pubmed/32731393
http://dx.doi.org/10.3390/cells9081791
_version_ 1783577633005502464
author Bajc Česnik, Ana
Motaln, Helena
Rogelj, Boris
author_facet Bajc Česnik, Ana
Motaln, Helena
Rogelj, Boris
author_sort Bajc Česnik, Ana
collection PubMed
description Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder, characterized by cytoplasmic inclusions of RNA-binding protein TDP-43. Despite decades of research and identification of more than 50 genes associated with amyotrophic lateral sclerosis (ALS), the cause of TDP-43 translocation from the nucleus and its aggregation in the cytoplasm still remains unknown. Our study addressed the impact of selected ALS-associated genes on TDP-43 aggregation behavior in wild-type and aggregation prone TDP-43 in vitro cell models. These were developed by deleting TDP-43 nuclear localization signal and stepwise shortening its low-complexity region. The SH-SY5Y cells were co-transfected with the constructs of aggregation-prone TDP-43 and wild-type or mutant ALS-associated genes hnRNPA1, MATR3, VCP or UBQLN2. The investigated genes displayed a unique impact on TDP-43 aggregation, generating distinct types of cytoplasmic inclusions, similar to those already described as resembling prion strains, which could represent the basis for neurodegenerative disease heterogeneity.
format Online
Article
Text
id pubmed-7465640
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-74656402020-09-04 The Impact of ALS-Associated Genes hnRNPA1, MATR3, VCP and UBQLN2 on the Severity of TDP-43 Aggregation Bajc Česnik, Ana Motaln, Helena Rogelj, Boris Cells Article Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder, characterized by cytoplasmic inclusions of RNA-binding protein TDP-43. Despite decades of research and identification of more than 50 genes associated with amyotrophic lateral sclerosis (ALS), the cause of TDP-43 translocation from the nucleus and its aggregation in the cytoplasm still remains unknown. Our study addressed the impact of selected ALS-associated genes on TDP-43 aggregation behavior in wild-type and aggregation prone TDP-43 in vitro cell models. These were developed by deleting TDP-43 nuclear localization signal and stepwise shortening its low-complexity region. The SH-SY5Y cells were co-transfected with the constructs of aggregation-prone TDP-43 and wild-type or mutant ALS-associated genes hnRNPA1, MATR3, VCP or UBQLN2. The investigated genes displayed a unique impact on TDP-43 aggregation, generating distinct types of cytoplasmic inclusions, similar to those already described as resembling prion strains, which could represent the basis for neurodegenerative disease heterogeneity. MDPI 2020-07-28 /pmc/articles/PMC7465640/ /pubmed/32731393 http://dx.doi.org/10.3390/cells9081791 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bajc Česnik, Ana
Motaln, Helena
Rogelj, Boris
The Impact of ALS-Associated Genes hnRNPA1, MATR3, VCP and UBQLN2 on the Severity of TDP-43 Aggregation
title The Impact of ALS-Associated Genes hnRNPA1, MATR3, VCP and UBQLN2 on the Severity of TDP-43 Aggregation
title_full The Impact of ALS-Associated Genes hnRNPA1, MATR3, VCP and UBQLN2 on the Severity of TDP-43 Aggregation
title_fullStr The Impact of ALS-Associated Genes hnRNPA1, MATR3, VCP and UBQLN2 on the Severity of TDP-43 Aggregation
title_full_unstemmed The Impact of ALS-Associated Genes hnRNPA1, MATR3, VCP and UBQLN2 on the Severity of TDP-43 Aggregation
title_short The Impact of ALS-Associated Genes hnRNPA1, MATR3, VCP and UBQLN2 on the Severity of TDP-43 Aggregation
title_sort impact of als-associated genes hnrnpa1, matr3, vcp and ubqln2 on the severity of tdp-43 aggregation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465640/
https://www.ncbi.nlm.nih.gov/pubmed/32731393
http://dx.doi.org/10.3390/cells9081791
work_keys_str_mv AT bajccesnikana theimpactofalsassociatedgeneshnrnpa1matr3vcpandubqln2ontheseverityoftdp43aggregation
AT motalnhelena theimpactofalsassociatedgeneshnrnpa1matr3vcpandubqln2ontheseverityoftdp43aggregation
AT rogeljboris theimpactofalsassociatedgeneshnrnpa1matr3vcpandubqln2ontheseverityoftdp43aggregation
AT bajccesnikana impactofalsassociatedgeneshnrnpa1matr3vcpandubqln2ontheseverityoftdp43aggregation
AT motalnhelena impactofalsassociatedgeneshnrnpa1matr3vcpandubqln2ontheseverityoftdp43aggregation
AT rogeljboris impactofalsassociatedgeneshnrnpa1matr3vcpandubqln2ontheseverityoftdp43aggregation