Converging mechanisms in ALS and FTD: Disrupted RNA and protein homeostasis

By Shuo-Chien Ling, M. Polymenidou, D. Cleveland. Neuron, 2013

1,720 citations recorded by the source corpus.

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 feed-forward loop including cell-to-cell prion-like spread that may represent the mechanism for relentless disease progression.

Subfields: Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/e0c8344a16e1ec69584cc1193709c4f897929979

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Citations in the corpus

Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis (2019, background): “TDP-43-RNA Interactions TDP-43 has versatile functions and it is involved in several steps of RNA metabolism such as: transcription, translation, mRNA transport, mRNA stabilization, microRNA (miRNA) and long non-coding RNA (lncRNA) processing etc. (Ling et al., 2013; Coyne et al., 2017) (Figure 3).”
Hallmarks of neurodegenerative diseases. (2023, neutral): “19,54,56,57,200,201,203,205,208 Defects in RNA metabolism/ homeostasis lead to defects in RNA driven processes and RNA transport, as well as to the formation of characteristic stress granules (SGs) that involve ribonucleoproteins (RNPs).”
An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex (2014, background): “Rather, it is a disease of the spinal cord in which astrocytes, microglia, and oligodendrocytes all contribute to disease progression (Ling et al., 2013).”
Residue-by-residue view of in vitro FUS granules that bind the C-terminal domain of RNA polymerase II (2015, neutral): “mutations located within the regions coding for FUS LC are linked to ALS (Belzil et al., 2009; Cruts et al., 2012; Ling et al., 2013; Ticozzi et al., 2009), including G156E, which increases FUS aggregation propensity in vitro and in cell culture (Nomura et al.”
A census of human RNA-binding proteins (2014, background): “sclerosis, a motor neuron disease leading to muscle atrophy (Anthony and Gallo, 2010; LagierTourenne et al., 2010; Lee et al., 2012; Ling et al., 2013).”