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

Shuo-Chien Ling1, Magdalini Polymenidou, Don W Cleveland

  • 1Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093-0670, USA.

Neuron
|August 13, 2013
PubMed

Insights

Genetic discoveries reveal shared causes for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These neurodegenerative diseases involve linked RNA and protein processing disruptions, potentially spreading through prion-like mechanisms.

Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are distinct neurodegenerative disorders.
  • Recent genetic discoveries highlight shared underlying mechanisms between ALS and FTD.
  • Key molecular players like TDP-43 and C9ORF72 expansions are implicated in both diseases.

Purpose of the Study:

  • To explore the interconnectedness of RNA processing and protein homeostasis in ALS and FTD.
  • To propose a unifying mechanism for the progression of these related neurodegenerative diseases.

Main Methods:

  • Review of genetic and molecular findings in ALS and FTD.
  • Analysis of common molecular pathways, including TDP-43, FUS/TLS, ubiquilin-2, VCP, and C9ORF72.
  • Conceptual model development for disease progression.

Main Results:

  • ALS and FTD share common genetic causes and molecular signatures.
  • Dysregulation of RNA processing and protein homeostasis are central to both disorders.
  • A feedforward loop involving these processes, potentially including prion-like spread, drives disease progression.

Conclusions:

  • RNA processing and protein homeostasis are intrinsically linked in ALS and FTD.
  • Cell-to-cell prion-like spread may explain the relentless progression of these neurodegenerative conditions.
  • Understanding these shared mechanisms offers new avenues for therapeutic intervention.

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