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
Nat Rev Drug Discov. 2018-08-17; 17(9): 660-688
DOI: 10.1038/nrd.2018.109

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1. 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

Boland B(1), Yu WH(2), Corti O(3), Mollereau B(4), Henriques A(5), Bezard E(6),
Pastores GM(7), Rubinsztein DC(8), Nixon RA(9)(10), Duchen MR(11), Mallucci
GR(12), Kroemer G(13)(14)(15)(16)(17)(18)(19), Levine B(20)(21), Eskelinen
EL(22), Mochel F(23), Spedding M(24), Louis C(25), Martin OR(26), Millan MJ(25).

Author information:
(1)Department of Pharmacology and Therapeutics, University College Cork, Cork,
(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.

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.

DOI: 10.1038/nrd.2018.109
PMID: 30116051

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