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RNA-binding proteins in neurodegeneration: mechanisms in aggregate

Conlon, Erin G., Manley, James L.·2017·Genes & Development
DOI 10.1101/gad.304055.117PMC PMC5630017
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Abstract

Neurodegeneration is a leading cause of death in the developed world and a natural, albeit unfortunate, consequence of longer-lived populations. Despite great demand for therapeutic intervention, it is often the case that these diseases are insufficiently understood at the basic molecular level. What little is known has prompted much hopeful speculation about a generalized mechanistic thread that ties these disparate conditions together at the subcellular level and can be exploited for broad curative benefit. In this review, we discuss a prominent theory supported by genetic and pathological changes in an array of neurodegenerative diseases: that neurons are particularly vulnerable to disruption of RNA-binding protein dosage and dynamics. Here we synthesize the progress made at the clinical, genetic, and biophysical levels and conclude that this perspective offers the most parsimonious explanation for these mysterious diseases. Where appropriate, we highlight the reciprocal benefits of cross-disciplinary collaboration between disease specialists and RNA biologists as we envision a future in which neurodegeneration declines and our understanding of the broad importance of RNA processing deepens.

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Figure 1. Overview of diseases and genes covered. Top-down schematic of neurodegeneration illustrating the tissue-wide phenomena and the genetic and molecular changes that occur at the subcellular level. (Left) Approximate sites of pathology and degenerating neurons in diseases covered in this review, including amyotrophic lateral sclerosis (ALS), spinocerebellar ataxia type 36 (SCA36), spinal muscular atrophy (SMA), frontotemporal dementia (FTD), Huntington's disease (HD), Huntington's disease-like 2 (HDL2), and myotonic dystrophy type 1 (DM1) and DM2. (Right) Mutations at the DNA result in a variety of changes at the level of RNA processing, such as repression of cryptic splicing (i), formation of exonic splicing silencers (ii), formation of hairpin structures that trigger RNA silencing pathways and sequester proteins (iii), formation of stable G-quadruplex (G-Q) structures that can form aggregates with RBPs (iv), mutations in RBPs that affect their RNA processing functions (v), and formation of aggregation-prone polyglutamine (polyQ) and dipeptide repeat (DPR) proteins (vi,vii). Genes harboring mutations are categorized as being RBP-encoding genes (TARDBP, FUS, hnRNP A1/A2B1, EWSR1, and MATR3 in ALS), noncoding expansions (C9ORF72 in ALS–FTD, FMR1 in fragile X syndrome and fragile X-associated tremor/ataxia syndrome, NOP56 in SCA36, and DMPK and CNBP in DM1 and DM2, respectively) or coding expansions (HTT in HD, JPH3 in HDL2, ATXN2 in spinocerebellar ataxia type 2 and ALS, and AR in X-linked spinal and bulbar muscular atrophy). Nucleotide repeat units for each noncoding and coding expansion are in quotations.
Figure 1. Overview of diseases and genes covered. Top-down schematic of neurodegeneration illustrating the tissue-wide phenomena and the genetic and molecular changes that occur at the subcellular level. (Left) Approximate sites of pathology and degenerating neurons in diseases covered in this review, including amyotrophic lateral sclerosis (ALS), spinocerebellar ataxia type 36 (SCA36), spinal muscular atrophy (SMA), frontotemporal dementia (FTD), Huntington's disease (HD), Huntington's disease-like 2 (HDL2), and myotonic dystrophy type 1 (DM1) and DM2. (Right) Mutations at the DNA result in a variety of changes at the level of RNA processing, such as repression of cryptic splicing (i), formation of exonic splicing silencers (ii), formation of hairpin structures that trigger RNA silencing pathways and sequester proteins (iii), formation of stable G-quadruplex (G-Q) structures that can form aggregates with RBPs (iv), mutations in RBPs that affect their RNA processing functions (v), and formation of aggregation-prone polyglutamine (polyQ) and dipeptide repeat (DPR) proteins (vi,vii). Genes harboring mutations are categorized as being RBP-encoding genes (TARDBP, FUS, hnRNP A1/A2B1, EWSR1, and MATR3 in ALS), noncoding expansions (C9ORF72 in ALS–FTD, FMR1 in fragile X syndrome and fragile X-associated tremor/ataxia syndrome, NOP56 in SCA36, and DMPK and CNBP in DM1 and DM2, respectively) or coding expansions (HTT in HD, JPH3 in HDL2, ATXN2 in spinocerebellar ataxia type 2 and ALS, and AR in X-linked spinal and bulbar muscular atrophy). Nucleotide repeat units for each noncoding and coding expansion are in quotations.CC BY-NC · PubMed Central
Figure 2. Functional domains of the RBPs TDP-43 and FUS and their cellular roles. Domain architecture of the disease-related proteins TDP-43 and FUS, with emphasis on the prion-like domains (PrLDs) that contribute to liquid–liquid phase separation, represented by a liquid droplet. Various cellular roles of these proteins, including nuclear–cytoplasmic shuttling, pre-mRNA processing, hnRNP interactions, mRNP granule formation, and amyloid-like fibrillization, are diagrammed, with the domains implicated in these processes highlighted.
Figure 2. Functional domains of the RBPs TDP-43 and FUS and their cellular roles. Domain architecture of the disease-related proteins TDP-43 and FUS, with emphasis on the prion-like domains (PrLDs) that contribute to liquid–liquid phase separation, represented by a liquid droplet. Various cellular roles of these proteins, including nuclear–cytoplasmic shuttling, pre-mRNA processing, hnRNP interactions, mRNP granule formation, and amyloid-like fibrillization, are diagrammed, with the domains implicated in these processes highlighted.CC BY-NC · PubMed Central

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Cited by

Metadata

Authors
Conlon, E. G., & Manley, J. L.
Venue
Genes & Development
Publisher
Cold Spring Harbor Laboratory
Published
2017-08-01
Volume
31
Issue
15
Pages
1509-1528
ISSN
  • 0890-9369
  • 1549-5477
DOI
10.1101/gad.304055.117
PMC
PMC5630017
Cited by
231
References
27
Language
en
Funders
National Institutes of Health (R35 GM118136)

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