RNA-binding proteins implicated in neurodegenerative diseases

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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Interplay of RNA-Binding Proteins and microRNAs in Neurodegenerative Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms22105292 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5292

Author(s):

Chisato Kinoshita ◽

Noriko Kubota ◽

Koji Aoyama

Keyword(s):

Neurodegenerative Diseases ◽

Protein Misfolding ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Critical Role ◽

Mirna Biogenesis ◽

Brain Functions ◽

Number Of Patients ◽

Protein Misfolding And Aggregation

The number of patients with neurodegenerative diseases (NDs) is increasing, along with the growing number of older adults. This escalation threatens to create a medical and social crisis. NDs include a large spectrum of heterogeneous and multifactorial pathologies, such as amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and multiple system atrophy, and the formation of inclusion bodies resulting from protein misfolding and aggregation is a hallmark of these disorders. The proteinaceous components of the pathological inclusions include several RNA-binding proteins (RBPs), which play important roles in splicing, stability, transcription and translation. In addition, RBPs were shown to play a critical role in regulating miRNA biogenesis and metabolism. The dysfunction of both RBPs and miRNAs is often observed in several NDs. Thus, the data about the interplay among RBPs and miRNAs and their cooperation in brain functions would be important to know for better understanding NDs and the development of effective therapeutics. In this review, we focused on the connection between miRNAs, RBPs and neurodegenerative diseases.

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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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