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Nat Rev Drug Discov. 2018 Sep;17(9):660-688. doi: 10.1038/nrd.2018.109. Epub 2018 Aug 17.

Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing.

Author information

1
Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland.
2
Department of Pathology and Cell Biology, Taub Institute for Alzheimer's Disease Research, Columbia University, New York, NY, USA.
3
ICM Institute for Brain and Spinal Cord, Paris, France.
4
Université de Lyon, ENSL, UCBL, CNRS, LBMC, Lyon, France.
5
Department of Pharmacology, Neuro-Sys, Gardanne, France.
6
CNRS, Institut des Maladies Neurodégénératives, Bordeaux, France.
7
Department of Metabolic Diseases, Mater Misericordiae University Hospital, Dublin, Ireland.
8
Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge and UK Dementia Research Institute, Cambridge Biomedical Campus, Cambridge, UK.
9
Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY, USA.
10
Departments of Psychiatry and Cell Biology, New York University School of Medicine, New York, NY, USA.
11
UCL Consortium for Mitochondrial Research and Department of Cell and Developmental Biology, University College London, London, UK.
12
Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
13
Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France.
14
Université Pierre et Marie Curie/Paris VI, Paris, France.
15
Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.
16
INSERM U1138, Paris, France.
17
Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.
18
Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.
19
Pôle de Biologie, Hopitâl Européen George Pompidou (AP-HP), Paris, France.
20
Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, TX, USA.
21
Howard Hughes Medical Institute, Dallas, TX, USA.
22
Division of Biochemistry, University of Turku, Turku, Finland.
23
INSERM U 1127, Brain and Spine Institute, Paris, France.
24
Spedding Research Solutions SARL, Le Vesinet, France.
25
Centre for Therapeutic Innovation in Neuropsychiatry, IDR Servier, 78290 Croissy sur Seine, France.
26
Université d'Orléans & CNRS, Institut de Chimie Organique et Analytique (ICOA), Orléans, France.

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.

PMID:
30116051
DOI:
10.1038/nrd.2018.109

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