Connecting RNA-Modifying Similarities of TDP-43, FUS, and SOD1 with MicroRNA Dysregulation Amidst A Renewed Network Perspective of Amyotrophic Lateral Sclerosis Proteinopathy
Beyond traditional approaches in understanding amyotrophic lateral sclerosis (ALS), multiple recent studies in RNA-binding proteins (RBPs)—including transactive response DNA-binding protein (TDP-43) and fused in sarcoma (FUS)—have instigated an interest in their function and prion-like properties. G...
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MDPI AG
2020-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/10/3464 |
| _version_ | 1797568063958155264 |
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| author | Jade Pham Matt Keon Samuel Brennan Nitin Saksena |
| author_facet | Jade Pham Matt Keon Samuel Brennan Nitin Saksena |
| author_sort | Jade Pham |
| collection | DOAJ |
| description | Beyond traditional approaches in understanding amyotrophic lateral sclerosis (ALS), multiple recent studies in RNA-binding proteins (RBPs)—including transactive response DNA-binding protein (TDP-43) and fused in sarcoma (FUS)—have instigated an interest in their function and prion-like properties. Given their prominence as hallmarks of a highly heterogeneous disease, this prompts a re-examination of the specific functional interrelationships between these proteins, especially as pathological SOD1—a non-RBP commonly associated with familial ALS (fALS)—exhibits similar properties to these RBPs including potential RNA-regulatory capabilities. Moreover, the cytoplasmic mislocalization, aggregation, and co-aggregation of TDP-43, FUS, and SOD1 can be identified as proteinopathies akin to other neurodegenerative diseases (NDs), eliciting strong ties to disrupted RNA splicing, transport, and stability. In recent years, microRNAs (miRNAs) have also been increasingly implicated in the disease, and are of greater significance as they are the master regulators of RNA metabolism in disease pathology. However, little is known about the role of these proteins and how they are regulated by miRNA, which would provide mechanistic insights into ALS pathogenesis. This review seeks to discuss current developments across TDP-43, FUS, and SOD1 to build a detailed snapshot of the network pathophysiology underlying ALS while aiming to highlight possible novel therapeutic targets to guide future research. |
| first_indexed | 2024-03-10T19:51:05Z |
| format | Article |
| id | doaj.art-ef2bdf5cebf444379d8e794405b7abe4 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T19:51:05Z |
| publishDate | 2020-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-ef2bdf5cebf444379d8e794405b7abe42023-11-20T00:26:20ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-05-012110346410.3390/ijms21103464Connecting RNA-Modifying Similarities of TDP-43, FUS, and SOD1 with MicroRNA Dysregulation Amidst A Renewed Network Perspective of Amyotrophic Lateral Sclerosis ProteinopathyJade Pham0Matt Keon1Samuel Brennan2Nitin Saksena3Faculty of Medicine, The University of New South Wales, Kensington, Sydney, NSW 2033, AustraliaIggy Get Out, Neurodegenerative Disease Section, Darlinghurst, Sydney, NSW 2010, AustraliaIggy Get Out, Neurodegenerative Disease Section, Darlinghurst, Sydney, NSW 2010, AustraliaIggy Get Out, Neurodegenerative Disease Section, Darlinghurst, Sydney, NSW 2010, AustraliaBeyond traditional approaches in understanding amyotrophic lateral sclerosis (ALS), multiple recent studies in RNA-binding proteins (RBPs)—including transactive response DNA-binding protein (TDP-43) and fused in sarcoma (FUS)—have instigated an interest in their function and prion-like properties. Given their prominence as hallmarks of a highly heterogeneous disease, this prompts a re-examination of the specific functional interrelationships between these proteins, especially as pathological SOD1—a non-RBP commonly associated with familial ALS (fALS)—exhibits similar properties to these RBPs including potential RNA-regulatory capabilities. Moreover, the cytoplasmic mislocalization, aggregation, and co-aggregation of TDP-43, FUS, and SOD1 can be identified as proteinopathies akin to other neurodegenerative diseases (NDs), eliciting strong ties to disrupted RNA splicing, transport, and stability. In recent years, microRNAs (miRNAs) have also been increasingly implicated in the disease, and are of greater significance as they are the master regulators of RNA metabolism in disease pathology. However, little is known about the role of these proteins and how they are regulated by miRNA, which would provide mechanistic insights into ALS pathogenesis. This review seeks to discuss current developments across TDP-43, FUS, and SOD1 to build a detailed snapshot of the network pathophysiology underlying ALS while aiming to highlight possible novel therapeutic targets to guide future research.https://www.mdpi.com/1422-0067/21/10/3464microRNAamyotrophic lateral sclerosisRNA metabolismTDP-43FUSSOD1 |
| spellingShingle | Jade Pham Matt Keon Samuel Brennan Nitin Saksena Connecting RNA-Modifying Similarities of TDP-43, FUS, and SOD1 with MicroRNA Dysregulation Amidst A Renewed Network Perspective of Amyotrophic Lateral Sclerosis Proteinopathy International Journal of Molecular Sciences microRNA amyotrophic lateral sclerosis RNA metabolism TDP-43 FUS SOD1 |
| title | Connecting RNA-Modifying Similarities of TDP-43, FUS, and SOD1 with MicroRNA Dysregulation Amidst A Renewed Network Perspective of Amyotrophic Lateral Sclerosis Proteinopathy |
| title_full | Connecting RNA-Modifying Similarities of TDP-43, FUS, and SOD1 with MicroRNA Dysregulation Amidst A Renewed Network Perspective of Amyotrophic Lateral Sclerosis Proteinopathy |
| title_fullStr | Connecting RNA-Modifying Similarities of TDP-43, FUS, and SOD1 with MicroRNA Dysregulation Amidst A Renewed Network Perspective of Amyotrophic Lateral Sclerosis Proteinopathy |
| title_full_unstemmed | Connecting RNA-Modifying Similarities of TDP-43, FUS, and SOD1 with MicroRNA Dysregulation Amidst A Renewed Network Perspective of Amyotrophic Lateral Sclerosis Proteinopathy |
| title_short | Connecting RNA-Modifying Similarities of TDP-43, FUS, and SOD1 with MicroRNA Dysregulation Amidst A Renewed Network Perspective of Amyotrophic Lateral Sclerosis Proteinopathy |
| title_sort | connecting rna modifying similarities of tdp 43 fus and sod1 with microrna dysregulation amidst a renewed network perspective of amyotrophic lateral sclerosis proteinopathy |
| topic | microRNA amyotrophic lateral sclerosis RNA metabolism TDP-43 FUS SOD1 |
| url | https://www.mdpi.com/1422-0067/21/10/3464 |
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