Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing

Barry Boland, Wai Haung Yu, Olga Corti, Bertrand Mollereau, Alexandre Henriques, Erwan Bezard, Greg M. Pastores, David C. Rubinsztein, Ralph A. Nixon, Michael R. Duchen, Giovanna R. Mallucci, Guido Kroemer, Beth Levine, Eeva Liisa Eskelinen, Fanny Mochel, Michael Spedding, Caroline Louis, Olivier R. Martin, Mark J. Millan

Research output: Contribution to journalReview article

95 Scopus citations

Abstract

Neurodegenerative disorders of ageing (NDAs) such as Alzheimer disease, Parkinson disease, frontotemporal dementia, Huntington disease and amyotrophic lateral sclerosis represent a major socio-economic challenge in view of their high prevalence yet poor treatment. They are often called ‘proteinopathies’ owing to the presence of misfolded and aggregated proteins that lose their physiological roles and acquire neurotoxic properties. One reason underlying the accumulation and spread of oligomeric forms of neurotoxic proteins is insufficient clearance by the autophagic–lysosomal network. Several other clearance pathways are also compromised in NDAs: chaperone-mediated autophagy, the ubiquitin–proteasome system, extracellular clearance by proteases and extrusion into the circulation via the blood–brain barrier and glymphatic system. This article focuses on emerging mechanisms for promoting the clearance of neurotoxic proteins, a strategy that may curtail the onset and slow the progression of NDAs.

Original languageEnglish (US)
Pages (from-to)660-688
Number of pages29
JournalNature Reviews Drug Discovery
Volume17
Issue number9
DOIs
StatePublished - Sep 1 2018

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

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    Boland, B., Yu, W. H., Corti, O., Mollereau, B., Henriques, A., Bezard, E., Pastores, G. M., Rubinsztein, D. C., Nixon, R. A., Duchen, M. R., Mallucci, G. R., Kroemer, G., Levine, B., Eskelinen, E. L., Mochel, F., Spedding, M., Louis, C., Martin, O. R., & Millan, M. J. (2018). Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing. Nature Reviews Drug Discovery, 17(9), 660-688. https://doi.org/10.1038/nrd.2018.109