Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis.
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.
Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093-0670, USA.
Shuo-Chien
SC
Ling
Magdalini
M
Polymenidou
Don W
DW
Cleveland
D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D000071183:Autophagy-Related Proteins; D000073885:C9orf72 Protein; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D057180:Frontotemporal Dementia / Q000235:genetics*; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012313:RNA / Q000378:metabolism*; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism; D000074405:Valosin Containing Protein
D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D011506:Proteins; D034702:RNA-Binding Protein FUS; C405662:UBQLN2 protein, human; D014452:Ubiquitins; D012313:RNA; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein