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Autophagy in acute brain injury

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From Nature Reviews Neuroscience

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Key Points

  • Autophagy is an evolutionarily old mechanism through which all eukaryotic cells, including neurons, remove supernumerary, ectopic or damaged cytoplasmic materials.

  • By favouring the re-establishment of cellular homeostasis, autophagy supports the survival of neurons exposed to specific forms of acute injury, such as methamphetamine intoxication, spinal cord injury and subarachnoid haemorrhage.

  • An autophagy-dependent form of cell death known as autosis contributes to the demise of neurons subjected to other forms of acute damage, such as neonatal hypoxia–ischaemia.

  • The actual impact of autophagic responses on the loss of neurons exposed to several other forms of acute damage (including adult stroke and traumatic brain injury) remains to be elucidated.

  • The limited specificity of pharmacological agents commonly used to manipulate autophagy and the lack of reliable biomarkers for ongoing autophagic responses in fixed samples underlie, at least in part, this gap in knowledge.

  • Additional investigations based on conditional-knockout models, refined pharmacological regimens and improved biomarkers of autophagy will clarify the actual role of autophagy in the neuronal response to various forms of acute injury.

Abstract

Autophagy is an evolutionarily ancient mechanism that ensures the lysosomal degradation of old, supernumerary or ectopic cytoplasmic entities. Most eukaryotic cells, including neurons, rely on proficient autophagic responses for the maintenance of homeostasis in response to stress. Accordingly, autophagy mediates neuroprotective effects following some forms of acute brain damage, including methamphetamine intoxication, spinal cord injury and subarachnoid haemorrhage. In some other circumstances, however, the autophagic machinery precipitates a peculiar form of cell death (known as autosis) that contributes to the aetiology of other types of acute brain damage, such as neonatal asphyxia. Here, we dissect the context-specific impact of autophagy on non-infectious acute brain injury, emphasizing the possible therapeutic application of pharmacological activators and inhibitors of this catabolic process for neuroprotection.

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Figure 1: General organization of autophagic responses.
Figure 2: Autophagy in the CNS.
Figure 3: Impact of autophagy on acute brain injury.

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Acknowledgements

G.K. is supported by the following agencies and institutes: the French Ligue Contre le Cancer (Équipe Labellisée); the French Agence National de la Recherche (ANR) — Projets Blancs; the ANR under the framework of E-Rare-2 (the ERA-Net for Research on Rare Diseases); the French Association pour la Recherche sur le Cancer (ARC); Cancéropôle Ile-de-France; the French Institut National du Cancer (INCa); the Fondation Bettencourt Schueller; the Fondation de France; the French Fondation pour la Recherche Médicale (FRM); the European Commission (ArtForce); the European Research Council (ERC); the LabEx Immuno-Oncology; the SIRIC (sites de recherche intégrée sur le cancer) Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); the Swiss Bridge Foundation; the Swiss Institute for Experimental Cancer Research (ISREC); and the Paris Alliance of Cancer Research Institutes (PACRI). K.B. is supported by the following agencies and institutes: the Swedish Research Council; the Swedish Childhood Cancer Foundation; the Swedish Cancer Foundation; the Swedish Brain Foundation; the Swedish Board of Radiation Safety; the Frimurare Barnhuset Foundation in Stockholm, Sweden; and governmental grants from the Swedish Agreement on Medical Education and Research (Avtal om läkarutbildning och forskning (ALF)).

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Author notes

  1. Lorenzo Galluzzi and José Manuel Bravo-San Pedro: These authors contributed equally to this work.

Authors and Affiliations

  1. Equipe 11 Labellisée Ligue Contre le Cancer, Centre de Recherche des Cordeliers, Paris, 75006, France

    Lorenzo Galluzzi, José Manuel Bravo-San Pedro & Guido Kroemer

  2. INSERM, U1138, Paris, 75006, France

    Lorenzo Galluzzi, José Manuel Bravo-San Pedro & Guido Kroemer

  3. Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, 75006, France

    Lorenzo Galluzzi, José Manuel Bravo-San Pedro & Guido Kroemer

  4. Université Pierre et Marie Curie/Paris VI, Paris, 75006, France

    Lorenzo Galluzzi, José Manuel Bravo-San Pedro & Guido Kroemer

  5. Gustave Roussy Comprehensive Cancer Institute, Villejuif, 94805, France

    Lorenzo Galluzzi & José Manuel Bravo-San Pedro

  6. Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital Q2:07, Stockholm, 17176, Sweden

    Klas Blomgren & Guido Kroemer

  7. Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, 94805, France

    Guido Kroemer

  8. Pôle de Biologie, Hopitâl Européen George Pompidou, AP-HP, Paris, 75015, France

    Guido Kroemer

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  1. Lorenzo Galluzzi
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Pharmacological activation of autophagy for neuroprotection. (PDF 998 kb)

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Pharmacological inhibition of autophagy for neuroprotection. (PDF 721 kb)

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Glossary

Regulated cell death

(RCD). A form of cell death that depends on genetically encoded machinery. In contrast to its accidental counterpart, RCD can be retarded or accelerated via specific pharmacological or genetic interventions.

Autophagic adaptor

A protein that physically interacts with lipidated LC3 as well as with autophagic receptors, hence facilitating the sequestration of autophagic cargoes within forming autophagosomes.

Calpains

A family of Ca2+-dependent, non-lysosomal cysteine proteases involved in processes as diverse as long-term synaptic potentiation and regulated cell death.

Mitochondrial permeability transition

(MPT). An abrupt increase in the permeability of the inner mitochondrial membrane to small solutes, resulting in the dissipation of the mitochondrial transmembrane potential and structural breakdown of the organelle.

Ischaemic preconditioning

A hormetic process in which sublethal hypoxic challenges establish resistance to subsequent exposure to lethal hypoxia, and which is known to robustly activate autophagy.

Trimethyltin

A tin-containing organic compound with prominent neurotoxic activity towards the hippocampus.

Locomotor sensitization

Long-lasting exacerbation of a psychostimulant-induced locomotor response, elicited by the repeated intermittent administration of the same psychoactive agent.

Caspase 3

A cysteine protease that precipitates apoptotic variants of regulated cell death, irrespective of the subcellular compartment in which they are initiated.

Cardiac glycoside

A natural compound, such as digoxin or digitoxin, that exerts positive inotropic effects and suppresses autosis as it inhibits the plasma membrane Na+/K+ ATPase.

Metformin

An oral medication currently licensed for the treatment of specific forms of diabetes. Metformin activates AMP-activated protein kinase and inhibits respiratory complex I.

Thapsigargin

A natural compound that promotes endoplasmic reticulum stress by operating as a non-competitive inhibitor of the sarco/endoplasmic reticulum Ca2+ ATPase.

Tunicamycin

A mixture of homologous nucleoside antibiotics that induce endoplasmic reticulum stress by blocking N-linked glycosylation.

Ischaemic penumbra

Ischaemic tissue potentially destined to infarction but not irreversibly injured in the course of stroke. The ischaemic penumbra is the main target of acute therapeutic interventions in stroke patients.

17-Allylamino-demethoxygeldanamycin

(17-AAG). A derivative of geldanamycin that targets heat shock protein 90 kDa-α family class A member 1 (HSP90AA1; also known as HSP90).

Necroptosis

A specific type of regulated cell death that depends on the activity of receptor-interacting serine/threonine kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL).

Systemic lupus erythematosus

An autoimmune disease that has a complex aetiology, involves multiple organs, progresses in an unpredictable manner and is usually treated with systemic immunosuppressants.

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Galluzzi, L., Bravo-San Pedro, J., Blomgren, K. et al. Autophagy in acute brain injury. Nat Rev Neurosci 17, 467–484 (2016). https://doi.org/10.1038/nrn.2016.51

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