The different autophagy degradation pathways and neurodegeneration
Neuron. 2022-03-01; 110(6): 935-966
DOI: 10.1016/j.neuron.2022.01.017
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Fleming A(1), Bourdenx M(2), Fujimaki M(3), Karabiyik C(3), Krause GJ(4), Lopez
A(1), Martín-Segura A(4), Puri C(3), Scrivo A(4), Skidmore J(5), Son SM(3),
Stamatakou E(3), Wrobel L(3), Zhu Y(3), Cuervo AM(6), Rubinsztein DC(7).
Author information:
(1)Department of Medical Genetics, University of Cambridge, Cambridge Institute
for Medical Research, The Keith Peters Building, Cambridge Biomedical Campus,
Hills Road, Cambridge CB2 0XY, UK; UK Dementia Research Institute, University of
Cambridge, Cambridge Institute for Medical Research, The Keith Peters Building,
Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK; Department of
Physiology, Development and Neuroscience, University of Cambridge, Downing
Street, Cambridge CB2 3DY, UK.
(2)Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293,
F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR
5293, F-33000 Bordeaux, France.
(3)Department of Medical Genetics, University of Cambridge, Cambridge Institute
for Medical Research, The Keith Peters Building, Cambridge Biomedical Campus,
Hills Road, Cambridge CB2 0XY, UK; UK Dementia Research Institute, University of
Cambridge, Cambridge Institute for Medical Research, The Keith Peters Building,
Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
(4)Department of Developmental and Molecular Biology, Albert Einstein College of
Medicine, Bronx, NY, USA; Institute for Aging Studies, Albert Einstein College of
Medicine, Bronx, NY, USA.
(5)The ALBORADA Drug Discovery Institute, University of Cambridge, Island
Research Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0AH,
UK.
(6)Department of Developmental and Molecular Biology, Albert Einstein College of
Medicine, Bronx, NY, USA; Institute for Aging Studies, Albert Einstein College of
Medicine, Bronx, NY, USA. Electronic address: .
(7)Department of Medical Genetics, University of Cambridge, Cambridge Institute
for Medical Research, The Keith Peters Building, Cambridge Biomedical Campus,
Hills Road, Cambridge CB2 0XY, UK; UK Dementia Research Institute, University of
Cambridge, Cambridge Institute for Medical Research, The Keith Peters Building,
Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK. Electronic
address: .
The term autophagy encompasses different pathways that route cytoplasmic material
to lysosomes for degradation and includes macroautophagy, chaperone-mediated
autophagy, and microautophagy. Since these pathways are crucial for degradation
of aggregate-prone proteins and dysfunctional organelles such as mitochondria,
they help to maintain cellular homeostasis. As post-mitotic neurons cannot dilute
unwanted protein and organelle accumulation by cell division, the nervous system
is particularly dependent on autophagic pathways. This dependence may be a
vulnerability as people age and these processes become less effective in the
brain. Here, we will review how the different autophagic pathways may protect
against neurodegeneration, giving examples of both polygenic and monogenic
diseases. We have considered how autophagy may have roles in normal CNS functions
and the relationships between these degradative pathways and different types of
programmed cell death. Finally, we will provide an overview of recently described
strategies for upregulating autophagic pathways for therapeutic purposes.
Copyright © 2022 Elsevier Inc. All rights reserved.
Conflict of interest statement: Declaration of interests D.C.R. is a consultant
for Aladdin Healthcare Technologies SE, Drishti Discoveries, Abbvie, PAQ
Therapeutics, MindRank AI, and Nido Biosciences. A.M.C. is a cofounder and
scientific adviser for Life Biosciences, consults for Generian Pharmaceuticals
and Cognition Therapeutics, and has US patent US9512092.