Abstract
Breakthrough discoveries identifying common genetic causes for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have transformed our view of these disorders. They share unexpectedly similar signatures, including dysregulation in common molecular players including TDP-43, FUS/TLS, ubiquilin-2, VCP, and expanded hexanucleotide repeats within the C9ORF72 gene. Dysfunction in RNA processing and protein homeostasis is an emerging theme. We present the case here that these two processes are intimately linked, with disease-initiated perturbation of either leading to further deviation of both protein and RNA homeostasis through a feedforward loop including cell-to-cell prion-like spread that may represent the mechanism for relentless disease progression.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Review
MeSH terms
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Adaptor Proteins, Signal Transducing
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Adenosine Triphosphatases / genetics
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Adenosine Triphosphatases / metabolism
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Amyotrophic Lateral Sclerosis / genetics*
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Animals
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Autophagy-Related Proteins
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C9orf72 Protein
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Frontotemporal Dementia / genetics*
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Homeostasis / genetics*
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Humans
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Models, Biological
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Mutation / genetics
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Proteins / genetics
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Proteins / metabolism*
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RNA / metabolism*
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RNA-Binding Protein FUS / genetics
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RNA-Binding Protein FUS / metabolism
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Ubiquitins / genetics
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Ubiquitins / metabolism
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Valosin Containing Protein
Substances
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Adaptor Proteins, Signal Transducing
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Autophagy-Related Proteins
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C9orf72 Protein
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C9orf72 protein, human
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Cell Cycle Proteins
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DNA-Binding Proteins
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Proteins
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RNA-Binding Protein FUS
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UBQLN2 protein, human
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Ubiquitins
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RNA
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Adenosine Triphosphatases
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VCP protein, human
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Valosin Containing Protein