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.

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Acknowledgements

The authors would like to thank S.-M. Rivet for help in the preparation of the figures, K. Duff, R. Jeggo, M.-C. Potier and C. Mannoury la Cour for helpful comments on the manuscript and M. Galliot and her colleagues in the Institut de recherche Servier (IDRS) Documentation Department for provision of papers relevant to this article. This article is based upon a small, focused symposium that was supported by an unrestricted grant from Advances in Neuroscience for Medical Innovation, which is affiliated with the Institut de Recherche Servier.

Author information

Author notes

    • Barry Boland
    • , Wai Haung Yu
    •  & Mark J. Millan

    These authors are equal first authors: Barry Boland, Wai Haung Yu, Mark J. Millan.

Affiliations

  1. Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland.

    • Barry Boland
  2. Department of Pathology and Cell Biology, Taub Institute for Alzheimer's Disease Research, Columbia University, New York, NY, USA.

    • Wai Haung Yu
  3. ICM Institute for Brain and Spinal Cord, Paris, France.

    • Olga Corti
  4. Université de Lyon, ENSL, UCBL, CNRS, LBMC, Lyon, France.

    • Bertrand Mollereau
  5. Department of Pharmacology, Neuro-Sys, Gardanne, France.

    • Alexandre Henriques
  6. CNRS, Institut des Maladies Neurodégénératives, Bordeaux, France.

    • Erwan Bezard
  7. Department of Metabolic Diseases, Mater Misericordiae University Hospital, Dublin, Ireland.

    • Greg M. Pastores
  8. Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge and UK Dementia Research Institute, Cambridge Biomedical Campus, Cambridge, UK.

    • David C. Rubinsztein
  9. Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY, USA.

    • Ralph A. Nixon
  10. Departments of Psychiatry and Cell Biology, New York University School of Medicine, New York, NY, USA.

    • Ralph A. Nixon
  11. UCL Consortium for Mitochondrial Research and Department of Cell and Developmental Biology, University College London, London, UK.

    • Michael R. Duchen
  12. Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

    • Giovanna R. Mallucci
  13. Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France.

    • Guido Kroemer
  14. Université Pierre et Marie Curie/Paris VI, Paris, France.

    • Guido Kroemer
  15. Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.

    • Guido Kroemer
  16. INSERM U1138, Paris, France.

    • Guido Kroemer
  17. Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.

    • Guido Kroemer
  18. Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.

    • Guido Kroemer
  19. Pôle de Biologie, Hopitâl Européen George Pompidou (AP-HP), Paris, France.

    • Guido Kroemer
  20. Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, TX, USA.

    • Beth Levine
  21. Howard Hughes Medical Institute, Dallas, TX, USA.

    • Beth Levine
  22. Division of Biochemistry, University of Turku, Turku, Finland.

    • Eeva-Liisa Eskelinen
  23. INSERM U 1127, Brain and Spine Institute, Paris, France.

    • Fanny Mochel
  24. Spedding Research Solutions SARL, Le Vesinet, France.

    • Michael Spedding
  25. Centre for Therapeutic Innovation in Neuropsychiatry, IDR Servier, 78290 Croissy sur Seine, France.

    • Caroline Louis
    •  & Mark J. Millan
  26. Université d'Orléans & CNRS, Institut de Chimie Organique et Analytique (ICOA), Orléans, France.

    • Olivier R. Martin

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Competing interests

M.J.M. is a full-time employee of Servier Pharmaceuticals and has no other competing interests to declare. E.B. has an equity stake in Motac Holding Ltd. and receives consultancy payments from Motac Neuroscience Ltd. D.C.R. is a consultant for E3Bio and has consulted for GlaxoSmithKline, AbbVie and AstraZeneca. He has received grant support from AbbVie and AstraZeneca. B.L. is a scientific founder of Casma Therapeutics. A.H. is a full-time employee of Neuro-Sys and has no other competing interests to declare. C.L. is a full-time employee of Servier Pharmaceuticals and has no other competing interests to declare. M.S. is a consultant for Servier Pharmaceuticals and President of Spedding Research Solutions SAS, a company performing research on potential therapies for amyotrophic lateral sclerosis. The author others declare no competing interests.

Corresponding author

Correspondence to Mark J. Millan.

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Glossary

Neurodegenerative disorders of ageing

(NDAs). A suite of neurodegenerative diseases including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis and frontotemporal dementia that typically are diagnosed in elderly individuals. Most cases are sporadic, but rare forms are associated with mutations (Table 1). Huntington disease is an exception in being purely genetic and having a somewhat earlier onset at 30–50 years of age.

Proteinopathies

A general term for disorders characterized by the build-up of excess, anomalously marked, misfolded and/or aggregated neurotoxic proteins like Aβ, tau or α-synuclein.

Amyloid-β

(Aβ). The major neurotoxic product of amyloid precursor protein (APP) processing, including Aβ fragment 42 (Aβ42), which deposits into extracellular plaques in Alzheimer disease. It is toxic as oligomers and protofibrils because it, for example, disrupts synaptic transmission, damages mitochondria and impedes proteasomal clearance.

Tau

A protein that stabilizes axonal microtubules. It is prone to cleavage, hyperphosphorylation and other modifications that trigger and/or follow microtubule dissociation. This leads to misfolding, oligomerization, synaptic mislocalization and interneuronal spreading. Aggregates, fibrils and intracellular neurofibrillary tangles are also formed.

α-Synuclein

A phospholipid-binding protein abundant in presynaptic terminals and involved in the release and regulation of synaptic vesicles. α-Synuclein is a major component of Lewy bodies (protein and lipid aggregates) in Parkinson disease. Its spread and accumulation in dopaminergic cell bodies and other cell types are typical features of the disease.

TAR DNA-binding protein 43

(TDP43). A normally nuclear protein that is associated with frontotemporal dementia and amyotrophic lateral sclerosis. In these diseases, it is found in the cytoplasm, where it aggregates.

Glymphatic system

A system that serves as a cerebrospinal fluid-driven mechanism for flushing extracellular pools of neurotoxic protein into the circulation; it involves perivascular drainage, astrocytes and the lymph system.

Blood–brain barrier

A physical and functional barrier that isolates the brain from the rest of the body. Certain nutrients, lipid vesicles and small molecules can enter, yet it excludes toxic elements that may damage the brain. It also ejects neurotoxic proteins and other unwanted material. Active transfer of neurotoxic proteins from the brain to the periphery involves specific classes of receptor and transporter.

Lysosomes

Acidic compartments for the degradation of proteins and other cellular constituents. Substrate breakdown yields products such as amino acids, sugars and lipids, which are recycled.

Aggresomes

Microtubule-associated inclusions located in the perinuclear region that contain mainly oligomeric, aggregated and ubiquitylated neurotoxic proteins together with ubiquitin-binding protein p62 and chaperones that aid in their formation. Aggresomes are often generated when ubiquitin–proteasome system activity is insufficient. Although they are protective when short-lived, they may be harmful in the long term and can morph into Lewy bodies in Parkinson disease. Aggresomes are cleared by the autophagic–lysosomal network.

Stress granules

Non-membrane enclosed, cytoplasmic agglomerates of ribonucleoproteins that store and protect mRNA during short-term cellular stress. Chaperones such as heat shock 70 kDa protein (HSP70) are involved in assembly and unfolding. In neurodegenerative diseases of ageing, neurotoxic proteins prolong the presence of stress granules and decrease their solubility, leading to aggregation or transformation into aggresomes.

Peroxisomes

Small (100 nm to 1 μm) organelles that oxidize long-chain fatty acids and aid in detoxification. They can be generated by budding-off from the endoplasmic reticulum and replicate via fission. Pexophagy refers to the autophagy of peroxisomes.

Autophagy-related genes

(ATGs). Genes and the molecular machinery for autophagy were characterized in yeast by Y. Ohsumi and others. The associated genes, identified using mutants, were originally termed Apg1–Apg15, yet ATG is now used. In view of conservation across species, this terminology is used for genes and/or proteins that regulate autophagy in humans as well.

5′-AMP-activated protein kinase

(AMPK). An enzyme involved in energy and nutrient sensing. When activated, AMPK triggers glucose uptake, lipogenesis and triglyceride synthesis. It is a major protein for sensing ATP deficits and initiating the autophagic–lysosomal network.

Mammalian target of rapamycin complex 1

(mTORC1). A multi-tasking serine/threonine-protein kinase that inhibits autophagy, mitophagy and proteasomal degradation. It also has other roles in, for example, controlling mRNA translation and protein synthesis. Mammalian target of rapamycin (mTOR) is part of mTORC1 together with several other regulatory and effector proteins.

Nicotinamide adenine dinucleotide

(NAD) A dinucleotide co-enzyme necessary for energy generation in all cell types. It is a cofactor for activation of NAD-dependent protein deacetylase sirtuin 1 (SIRT1) and is required for operation of the autophagic–lysosomal network. The oxidized and active form is NAD+.

Acetyl CoA

A cofactor involved in protein, carbohydrate and lipid metabolism. It is formed during glycolysis. It provides the acetyl group used by acetyltransferases like histone acetyltransferase p300 to acetylate autophagy-related gene (ATG) proteins, histones and other substrates such as tau.

RAS-related protein RAB7

(RAB7). A member of the GTPase RAS superfamily of monomeric G proteins, which participate in vesicular trafficking, vesicle formation, vesicle movement (actin-mediated and/or tubulin-mediated) and vesicular fusion, as in autophagosomal fusion with lysosomes.

SNARE

Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) refers to a complex of proteins including synaptobrevin, syntaxin, synaptosomal-associated protein 25 (SNAP-25) and synaptogamin. SNARE contributes to vesicle fusion by 'zippering' a donor vesicle (such as an autophagosome) onto the recipient compartment (such as the lysosome).

Phospholipase D1

(PLD1). Enzyme involved in the transformation of various lipids; it participates in the fusion of autophagosomes with lysosomes.

Lysosomal storage disorders

(LSDs). Diseases resulting from genetic mutations that lead to failure of lysosomal digestion and consequent accumulation of lipids, proteins and other non-digested material. Their pathology is not restricted to the brain, and the age of onset is much earlier than for sporadic, age-related neurodegenerative disorders.

Niemann–Pick type C disease

A lysosomal storage disorder triggered by a defect in the NPC1 gene responsible for cholesterol transport. Patients often display amyloid-β fragment 42 (Aβ42) and tau pathology, underpinning parallels to Alzheimer disease, in which cholesterol transport is likewise disrupted.

Heat shock cognate 71 kDa protein

(HSC70). A constitutively expressed chaperone that affects ATP-dependent nascent and/or unfolded protein folding. It specifically recognizes proteins with an exposed KFERQ-like sequence and delivers them to lysosome-associated membrane glycoprotein 2A (LAMP2A) on lysosomes, where, aided by other proteins, substrates are translocated to the lumen for degradation by chaperone-mediated autophagy.

KFERQ

The KFERQ motif on a protein is the principal criterion for capture followed by chaperone-mediated autophagy (CMA). Q refers to glutamine, although this sometimes may be an asparagine (N). The other residues are acidic (D and E), basic (K and R) or basic and/or hydrophobic (F). There are, however, variations, and post-translational modification can modify susceptibility of proteins bearing a KFERQ signal for CMA.

Amyloid precursor protein

(APP). A transmembrane protein highly expressed in neurons and involved in maintaining cell–cell contact. Successive cleavage by β-secretases and γ-secretases results in the formation of APP terminal fragments like C99, as well as amyloid-β fragment 42 (Aβ42) and related species of neurotoxic peptide.

Lipofuscin

A pigmented cellular inclusion composed of undigestedlysosomal contents, including oxidized and crosslinked proteins. This electron-dense, autofluorescent material is characteristic of ageing and neurodegenerative disorders of ageing and can be seen in all types of cerebral cell.

Unfolded protein response

(UPR). A protective response to help cells recover from cellular and endoplasmic reticulum stress. The UPR acts via three key effector proteins to modify gene transcription/mRNA translation. The UPR interrupts bulk protein synthesis, promotes the generation of chaperones for protein folding and increases degradation of misfolded proteins. Overactivation and protracted engagement of the UPR are harmful for neurons and are implicated in neurodegenerative disorders of ageing.

ALN dysfunction

Underactive autophagy is a term used when rates of autophagosome formation and cargo sequestration decrease below basal levels or fail to upregulate sufficiently under stress. Impaired autophagy occurs when lysosomal delivery, fusion or digestion of autophagosomes are compromised. Overactive autophagy is the overproduction of autophagosomes and excess autophagic–lysosomal network activity; this can lead to autosis.

Autosis

Autophagy-related cell death mediated principally by the Na+/K+-ATPase pump. This can occur with prolonged and excessive autophagy. It is triggered by hypoxia–ischaemia (as in stroke or traumatic brain injury), but its occurrence in neurodegenerative disorders of ageing is uncertain.

Apolipoprotein E allele 4

(APOE4). A robust genetic risk factor for Alzheimer disease compared with the more common APOE2 and APOE3 alleles. APOE is mainly secreted by astrocytes and binds lipids such as cholesterol, which are carried to neurons. APOE4 is also involved in transport of cholesterol-bound amyloid-β (Aβ) to the blood–brain barrier (APOE4 is less efficient than APOE2 or APOE3) and in driving synthesis of Aβ fragment 42 (Aβ42) (APOE4 is more potent than APOE2 or APOE3).

Presenilin 1

(PS1). A gene encoding the catalytic unit of the γ-secretase complex, which processes amyloid precursor protein (APP) into amyloid-β (Aβ). Mutations are associated with familial Alzheimer disease and in part reflect altered APP processing. In addition, reduced lysosomal acidification and autophagic–lysosomal network function may be involved owing to mutant presenilin 1-driven deficits in maturation and translocation of vacuolar-type H+-ATPase complex (v-ATPase) subunits to the lysosome.

Parkin

A component of the E3 ubiquitin ligase complex that binds to its partner PTEN-induced putative kinase protein 1 (PINK1) to facilitate the autophagic removal of dysfunctional mitochondria that have lost their membrane potential.

Gaucher disease

A primary, autosomal recessive lysosomal storage disease caused by mutations in the GBA1 gene, which encodes β-glucocerebrosidase (βGCase). There is a fivefold higher risk of Parkinson disease (PD) in affected carriers. The activity of βGCase is impaired in a subpopulation of patients with non-familial PD, which includes many patients who have genetic mutations related to lysosomal disruption.

Superoxide dismutase 1

(SOD1). A mitochondrial enzyme dedicated to the reduction of free radicals (reactive oxygen species). SOD1 mutations and dysfunction are seen in a subset of patients with amyotrophic lateral sclerosis.

CAG-expansion repeats

Proteins can contain multiple CAG repeats (CAG encodes glutamine (symbol Q)). When the number of CAG repeats is above normal (for example, greater than 35 for the huntingtin (Htt) protein), proteins aggregate, provoke cellular damage and trigger inherited, polyglutamine diseases such as Huntington disease, spinocerebellar ataxia 3/Joseph–Machado disease (involving the ataxin 3 protein) and spinal and bulbar muscular atrophy (involving the androgen receptor).

TAT–beclin 1

A synthetic peptide comprising 11 amino acids of the HIV transactivator of transcription (TAT) protein transduction domain, a diglycine linker and a (commonly 11-mer) sequence derived from amino acids 267–284 of beclin 1. It is cell penetrant and triggers autophagic–lysosomal network-mediated neurotoxic protein clearance without causing cytotoxicity, although higher concentrations may carry the risk of autosis.

Heat shock factor 1

(HSF1). A protein that occurs as a monomer in the nucleus and cytoplasm and is repressed by heat shock proteins such as heat shock 70 kDa protein (HSP70). Following disruption of proteostasis, heat shock proteins dissociate from HSF1 in order to aid protein folding. HSF1 then trimerizes and acts as a transcription factor to increase production of HSP70 and other neuroprotective proteins.

Exosomes

Small (30–120 nm), ceramide-rich vesicles formed mainly from multivesicular bodies. They are released with their contents (proteins, lipids, sugars and nucleic acids) into the extracellular space upon fusion with the plasma membrane. Exosomes contribute to the spread of neurotoxic proteins. Exosomes in cerebrospinal fluid, blood and urine are stable and useful as biomarkers.

Immunotherapies

Biological therapies that passively or actively boost the body's natural defences. Specific classes of antibody aim to neutralize neurotoxic proteins such as amyloid-β fragment 42 (Aβ42) or tau. Entrance to the brain is limited, but these antibodies may also act as a peripheral sink for neurotoxic proteins in the circulation. In the brain, antibodies probably act for the most part extrinsically to neurons.

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DOI

https://doi.org/10.1038/nrd.2018.109