Nuclear carrier and RNA-binding proteins in frontotemporal lobar degeneration associated with fused in sarcoma (FUS) pathological changes

Both RNA-binding proteins (RBPs) and translation are increasingly implicated in several neurodegenerative diseases, but their specific roles in promoting disease are not yet fully defined. This chapter critically evaluates the evidence that altered translation of specific mRNAs mediated by RNA-binding proteins plays an important role in driving specific neurodegenerative diseases. First, diseases are discussed where a causal role for RNA-binding proteins in disease appears solid, but whether this involves altered translation is less clear. The main foci here are TAR DNA-binding protein (TDP-43) and fused in sarcoma (FUS) in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Subsequently, diseases are presented where altered translation is believed to contribute, but involvement of RNA-binding proteins is less clear. These include Huntington’s and other repeat expansion disorders such as fragile X tremor/ataxia syndrome (FXTAS), where repeat-induced non-AUG-initiated (RAN) translation is a focus. The potential contribution of both canonical and non-canonical RBPs to altered translation in Parkinson’s disease is discussed. The chapter closes by proposing key research frontiers for the field to explore and outlining methodological advances that could help to address them.

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RNA Binding Proteins and the Pathogenesis of Frontotemporal Lobar Degeneration

Annual Review of Pathology Mechanisms of Disease ◽

10.1146/annurev-pathmechdis-012418-012955 ◽

2019 ◽

Vol 14 (1) ◽

pp. 469-495 ◽

Cited By ~ 9

Author(s):

Jeffrey W. Hofmann ◽

William W. Seeley ◽

Eric J. Huang

Keyword(s):

Frontotemporal Lobar Degeneration ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Low Complexity ◽

Compelling Evidence ◽

Abnormal Protein ◽

Early Onset Dementia ◽

Cellular Pathways ◽

Liquid Liquid Phase Separation

Frontotemporal dementia is a group of early onset dementia syndromes linked to underlying frontotemporal lobar degeneration (FTLD) pathology that can be classified based on the formation of abnormal protein aggregates involving tau and two RNA binding proteins, TDP-43 and FUS. Although elucidation of the mechanisms leading to FTLD pathology is in progress, recent advances in genetics and neuropathology indicate that a majority of FTLD cases with proteinopathy involving RNA binding proteins show highly congruent genotype–phenotype correlations. Specifically, recent studies have uncovered the unique properties of the low-complexity domains in RNA binding proteins that can facilitate liquid–liquid phase separation in the formation of membraneless organelles. Furthermore, there is compelling evidence that mutations in FTLD genes lead to dysfunction in diverse cellular pathways that converge on the endolysosomal pathway, autophagy, and neuroinflammation. Together, these results provide key mechanistic insights into the pathogenesis and potential therapeutic targets of FTLD.

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RNA-binding proteins with prion-like domains in health and disease

Biochemical Journal ◽

10.1042/bcj20160499 ◽

2017 ◽

Vol 474 (8) ◽

pp. 1417-1438 ◽

Cited By ~ 152

Author(s):

Alice Ford Harrison ◽

James Shorter

Keyword(s):

Phase Transitions ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Binding Protein ◽

Low Complexity ◽

Fused In Sarcoma ◽

Heterogeneous Nuclear Ribonucleoproteins ◽

Health And Disease ◽

Lateral Sclerosis

Approximately 70 human RNA-binding proteins (RBPs) contain a prion-like domain (PrLD). PrLDs are low-complexity domains that possess a similar amino acid composition to prion domains in yeast, which enable several proteins, including Sup35 and Rnq1, to form infectious conformers, termed prions. In humans, PrLDs contribute to RBP function and enable RBPs to undergo liquid–liquid phase transitions that underlie the biogenesis of various membraneless organelles. However, this activity appears to render RBPs prone to misfolding and aggregation connected to neurodegenerative disease. Indeed, numerous RBPs with PrLDs, including TDP-43 (transactivation response element DNA-binding protein 43), FUS (fused in sarcoma), TAF15 (TATA-binding protein-associated factor 15), EWSR1 (Ewing sarcoma breakpoint region 1), and heterogeneous nuclear ribonucleoproteins A1 and A2 (hnRNPA1 and hnRNPA2), have now been connected via pathology and genetics to the etiology of several neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal dementia, and multisystem proteinopathy. Here, we review the physiological and pathological roles of the most prominent RBPs with PrLDs. We also highlight the potential of protein disaggregases, including Hsp104, as a therapeutic strategy to combat the aberrant phase transitions of RBPs with PrLDs that likely underpin neurodegeneration.

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Fused in Sarcoma (FUS) in DNA Repair: Tango with Poly(ADP-ribose) Polymerase 1 and Compartmentalisation of Damaged DNA

International Journal of Molecular Sciences ◽

10.3390/ijms21197020 ◽

2020 ◽

Vol 21 (19) ◽

pp. 7020

Author(s):

Maria V. Sukhanova ◽

Anastasia S. Singatulina ◽

David Pastré ◽

Olga I. Lavrik

Keyword(s):

Dna Repair ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Neurological Diseases ◽

Rna Metabolism ◽

Dna Integrity ◽

Fused In Sarcoma ◽

Repair Pathways ◽

Dna Strand

The fused in sarcoma (FUS) protein combines prion-like properties with a multifunctional DNA/RNA-binding domain and has functions spanning the regulation of RNA metabolism, including transcription, pre-mRNA splicing, mRNA transport and translation. In addition to its roles in RNA metabolism, FUS is implicated in the maintenance of DNA integrity. In this review, we examine the participation of FUS in major DNA repair pathways, focusing on DNA repair associated with poly(ADP-ribosyl)ation events and on how the interaction of FUS with poly(ADP-ribose) may orchestrate transient compartmentalisation of DNA strand breaks. Unravelling how prion-like RNA-binding proteins control DNA repair pathways will deepen our understanding of the pathogenesis of some neurological diseases and cancer as well as provide the basis for the development of relevant innovative therapeutic technologies. This knowledge may also extend the range of applications of poly(ADP-ribose) polymerase inhibitors to the treatment of neurodegenerative diseases related to RNA-binding proteins in the cell, e.g., amyotrophic lateral sclerosis and frontotemporal lobar degeneration.

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Perturbations in Traffic: Aberrant Nucleocytoplasmic Transport at the Heart of Neurodegeneration

Cells ◽

10.3390/cells7120232 ◽

2018 ◽

Vol 7 (12) ◽

pp. 232 ◽

Cited By ~ 18

Author(s):

Birthe Fahrenkrog ◽

Amnon Harel

Keyword(s):

Neurodegenerative Diseases ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Nucleocytoplasmic Transport ◽

Nuclear Accumulation ◽

Nuclear Pore ◽

Nuclear Pore Complexes ◽

Loss Of Function ◽

Fused In Sarcoma

Neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Huntington’s disease (HD), are characterized by intracellular aggregation of proteins. In the case of ALS and FTD, these protein aggregates are found in the cytoplasm of affected neurons and contain certain RNA-binding proteins (RBPs), namely the TAR DNA-binding protein of 43 kDa (TDP-43) and the fused in sarcoma (FUS) gene product. TDP-43 and FUS are nuclear proteins and their displacement to the cytoplasm is thought to be adverse in at least two ways: loss-of-function in the nucleus and gain-of-toxicity in the cytoplasm. In the case of HD, expansion of a polyglutamine (polyQ) stretch within the N-terminal domain of the Huntingtin (HTT) protein leads to nuclear accumulation of polyQ HTT (or mHTT) and a toxic gain-of-function phenotype resulting in neurodegeneration. Numerous studies in recent years have provided evidence that defects in nucleocytoplasmic transport critically contribute to the pathology of these neurodegenerative diseases. A new mechanistic view is emerging, implicating three types of perturbations in normal cellular pathways that rely on nucleocytoplasmic transport: displacement of nuclear transport receptors and nucleoporins from nuclear pore complexes (NPCs), mislocalization and aggregation of RNA-binding proteins, and weakening of the chaperone activity of nuclear import receptors.

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