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Role and therapeutic potential of liquid-liquid phase separation in amyotrophic lateral sclerosis

期刊

JOURNAL OF MOLECULAR CELL BIOLOGY
卷 13, 期 1, 页码 15-28

出版社

OXFORD UNIV PRESS
DOI: 10.1093/jmcb/mjaa049

关键词

phase separation; stress granule; motor neuron; ALS therapy

资金

  1. VIB
  2. KU Leuven
  3. 'Fund for Scientific Research Flanders' (FWO-Vlaanderen)
  4. Agency for Innovation by Science and Technology in Flanders
  5. Thierry Latran Foundation
  6. 'Association Belge contre les Maladies neuro-Musculaires' (ABMM)
  7. Muscular Dystrophy Association (MDA)
  8. Target ALS
  9. ALS Liga Belgie (A Cure for ALS)
  10. ALS Association (ALSA)
  11. FWO-Vlaanderen
  12. Research Foundation Flanders (FWO) [G.0328.16N]
  13. VIB International Life Sciences PhD Program

向作者/读者索取更多资源

ALS is a late-onset neurodegenerative disease affecting motor neurons, with TDP-43 and FUS identified as LLPS proteins that form liquid droplets. Research is focused on understanding the underlying nature of this common pathology, with potential therapeutic strategies targeting LLPS for treating ALS.
Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disease selectively affecting motor neurons, leading to progressive paralysis. Although most cases are sporadic, similar to 10% are familial. Similar proteins are found in aggregates in sporadic and familial ALS, and over the last decade, research has been focused on the underlying nature of this common pathology. Notably, TDP-43 inclusions are found in almost all ALS patients, while FUS inclusions have been reported in some familial ALS patients. Both TDP-43 and FUS possess 'low-complexity domains' (LCDs) and are considered as 'intrinsically disordered proteins', which form liquid droplets in vitro due to the weak interactions caused by the LCDs. Dysfunctional 'liquid-liquid phase separation' (LLPS) emerged as a new mechanism linking ALS-related proteins to pathogenesis. Here, we review the current state of knowledge on ALS-related gene products associated with a proteinopathy and discuss their status as LLPS proteins. In addition, we highlight the therapeutic potential of targeting LLPS for treating ALS.

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