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Autophagy and Neurodegeneration: Pathogenic Mechanisms and Therapeutic Opportunities
Open accessAbstract
Autophagy is a conserved pathway that delivers cytoplasmic contents to the lysosome for degradation. Here we consider its roles in neuronal health and disease. We review evidence from mouse knockout studies demonstrating the normal functions of autophagy as a protective factor against neurodegeneration associated with intracytoplasmic aggregate-prone protein accumulation as well as other roles, including in neuronal stem cell differentiation. We then describe how autophagy may be affected in a range of neurodegenerative diseases. Finally, we describe how autophagy upregulation may be a therapeutic strategy in a wide range of neurodegenerative conditions and consider possible pathways and druggable targets that may be suitable for this objective.
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“and permanent or transient endogenous defects in autophagy have been associated with embryonic lethality, developmental defects, and multiple pathological disorders, including (but not limited to) neurodegeneration, cancer, and cardiovascular disorders [812–817].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [813]
In the citing paper
“Molecular and histopathologic analyses of patient tissues demonstrate mislocalized or accumulated autophagy machinery, pathogenic mutations underlying familial neurodegenerative diseases disable known autophagy-related factors, and genetically ablating autophagy effectors produce neurodegeneration in cell and animal model systems [74–81], supporting a role for autophagy dysfunction in the devel”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [80]
In the citing paper
“The autophagic process is essential in preserving the homeostatic requirements of post‐mitotic neurons, both at the central and at the peripheral nervous system levels (Menzies et al, 2017; Scrivo et al, 2018; Mallucci et al, 2020)”
From Autophagy in major human diseases (2021) · cites this paper as Menzies et al, 2017
In the citing paper
“By analogy, a comparable phenotype has been described in Atg16l1 hypomorphic mice (Lv et al, 2014; Wu et al, 2016; Menzies et al, 2017).”
From Autophagy in major human diseases (2021) · cites this paper as Menzies et al, 2017
In the citing paper
“Aβ is targeted for autophagy‐dependent degradation within the lysosome, explaining why activation of autophagy reduces the burden of Aβ plaques in rodents (Boland et al, 2008; Menzies et al, 2017; Meng et al, 2019).”
From Autophagy in major human diseases (2021) · cites this paper as Menzies et al, 2017
In the citing paper
“However, autophagy appears to be causally implicated in the PSEN1 (presenilin 1)‐mediated conversion of APP (amyloid beta precursor protein) into Aβ (Yu et al, 2005), as well as in the non‐canonical secretion of Aβ into the extracellular space (Nilsson et al, 2013; Menzies et al, 2017).”
From Autophagy in major human diseases (2021) · cites this paper as Menzies et al, 2017
In the citing paper
“While autophagy proteins have been shown to impact the clearance of protein aggregates in neurons, most likely by the canonical autophagic process of aggrephagy (Frake et al., 2015; Menzies et al., 2017; Qaisiya et al., 2017; Sarkar et al., 2007; Sarkar et al., 2009; Webb et al., 2003; Yamamoto and Simonsen, 2011), effects in microglia of the CNS are more likely due to LANDO.”
From LC3-Associated Endocytosis Facilitates β-Amyloid Clearance and Mitigates Neurodegeneration in Murine Alzheimer’s Disease (2019) · cites this paper as Menzies et al., 2017
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“[39], impaired neuronal mitochondrial metabolism decreases adenosine triphosphate (ATP) generation, elevates O2 free radicals, and increases the generation of extracellular Aβ and the phosphorylation of intracellular Tau proteins.”
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BackgroundPersistent remodeling and neurodegeneration in late-stage retinal degeneration
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BackgroundNovel Approaches for the Treatment of Alzheimer’s and Parkinson’s Disease
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The effects of metformin on autophagy
Lu, G., Wu, Z., Shang, J., Xie, Z., Chen, C., & zhang, C. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.111286 · Cited by 188
Wei, R., Mao, L., Xu, P., Zheng, X., Hackman, R. M., Mackenzie, G. G., & Wang, Y. (2018) · Food & Function · doi:10.1039/c8fo01397g · Cited by 176
Cao, Y., Li, Q., Liu, L., Wu, H., Huang, F., Wang, C., Lan, Y., Zheng, F., Xing, F., Zhou, Q., et al. (2019) · British Journal of Pharmacology · doi:10.1111/bph.14626 · Cited by 167
“Autophagy is an intracellular degradation event in which a portion of cytoplasm is sequestered into autophagosomes, which degrade proteins and cellular structures upon fusing with lysosomes (Klionsky, 2005; Mizushima, 2007).”
BackgroundLiquid–liquid phase separation in autophagy
Noda, N. N., Wang, Z., & Zhang, H. (2020) · The Journal of Cell Biology · doi:10.1083/jcb.202004062 · Cited by 175
“Aberrant accumulation of protein aggregates as a result of impaired autophagic degradation has been linked with aging and pathogenesis of various diseases (Levine et al., 2011; Menzies et al., 2017; Zhao and Zhang, 2019a).”
BackgroundColacurcio, D. J., Pensalfini, A., Jiang, Y., & Nixon, R. A. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.10.001 · Cited by 167
Autophagy and intermittent fasting: the connection for cancer therapy?
Antunes, F., Erustes, A. G., Costa, A. J., Nascimento, A. C., Bincoletto, C., Ureshino, R. P., Pereira, G. J. S., & Smaili, S. S. (2018) · Clinics · doi:10.6061/clinics/2018/e814s · Cited by 179
“Throughout the past decade, autophagy has attracted considerable attention as a potential target of pharmacological agents or dietary interventions that inhibit or activate this process for several human disorders, including infections and inflammatory diseases (22), neurodegeneration (23), metabolic and cardiovascula…”
BackgroundMolecular Mechanisms of Neuroinflammation in Aging and Alzheimer’s Disease Progression
Andronie-Cioară, F. L., Ardelean, A. I., Nistor-Cseppento, C. D., Jurcău, A., Jurcău, M. C., Pașcalău, N., & Marcu, F. M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24031869 · Cited by 170
Consensus Paper. Cerebellar Reserve: From Cerebellar Physiology to Cerebellar Disorders
Mitoma, H., Buffo, A., Gelfo, F., Guell, X., Fucà, E., Kakei, S., Lee, J., Manto, M. U., Petrosini, L., Shaikh, A. G., et al. (2019) · The Cerebellum · doi:10.1007/s12311-019-01091-9 · Cited by 171
“Significant dysfunctions in the autophagy pathway have been identified in several neurodegenerative diseases [158, 159].”
BackgroundThe aging lysosome: An essential catalyst for late-onset neurodegenerative diseases
Nixon, R. A. (2020) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2020.140443 · Cited by 149
“The dysfunction of autophagy in aging-related neurodegenerative disorders has been extensively reviewed (Boland et al., 2018; Menzies et al., 2017; Nixon, 2016; Nixon, 2013; Scrivo et al., 2018).”
BackgroundFarfel-Becker, T., Roney, J. C., Cheng, X.-T., Li, S., Cuddy, S. R., & Sheng, Z.-H. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.06.013 · Cited by 152
“…to the pathogenesis of major neurodegenerative diseases, including Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis (Nixon, 2013; Xie et al., 2015; Wong and Krainc, 2016; 2017; Menzies et al., 2017; Wang et al., 2018; Pitcairn et al., 2019; Klein and Mazzulli, 2018).”
Recent Insights into the Mitochondrial Role in Autophagy and Its Regulation by Oxidative Stress
Agujetas, V. R., de Dios, C., Pinilla, L. L., Marı́, M., Morales, A., & Colell, A. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/3809308 · Cited by 153
“The brain of individuals with these neurodegenerative proteinopathies also displays an accumulation of autophagosome-like structures, suggesting an impaired autophagic flux as the cause of the abnormal diseasespecific protein buildups [139].”
BackgroundSelvaraj, N. R., Nandan, D., Nair, B. J. B., Nair, V. A., Venugopal, P., & Aradhya, R. (2025) · Cells · doi:10.3390/cells14070511 · Cited by 163
“…increases oxidative stress [190] Autophagy Can promote both stemness maintenance and loss [189] Impairment contributes to protein aggregation [191] Genetic influence Oncogenes promote cell survival and growth (e.g., PARK7/DJ-1 antagonizing PTEN) [192] Tumor suppressor-like genes involved in…”
Wang, H., Chen, S., Zhang, Y., Xu, H., & Sun, H. (2019) · Nitric Oxide · doi:10.1016/j.niox.2019.07.004 · Cited by 147
Signal pathways in the treatment of Alzheimer’s disease with traditional Chinese medicine
Ding, M.-R., Qu, Y.-J., Hu, B., & An, H. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113208 · Cited by 145
Autophagy in neurodegeneration: New insights underpinning therapy for neurological diseases
Corti, O., Blomgren, K., Poletti, A., & Beart, P. M. (2020) · Journal of Neurochemistry · doi:10.1111/jnc.15002 · Cited by 141
“…continue to attract attention focusing on for example mTOR-dependent and-independent pathways, and broadly on signalling linked to Beclin1, Atg5, AMP-dependent protein kinase, PICALM and histone deacetylases (Shoji-Kawata et al. 2013, Hu et al. 2017, Menzies et al. 2017, Rahman & Rhim 2017).”
BackgroundAutophagy impairment in Parkinson’s disease
Karabiyik, C., Lee, M. J., & Rubinsztein, D. C. (2017) · Essays in Biochemistry · doi:10.1042/ebc20170023 · Cited by 141
“Mutations underlying various neurodegenerative diseases that manifest with intracytoplasmic protein aggregates have been shown to affect the clearance of these substrates by compromising autophagy (4).”
BackgroundSelf-citationNeurodegenerative Disease Tauopathies
Creekmore, B. C., Watanabe, R., & Lee, E. B. (2023) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-051222-120750 · Cited by 155
Zhang, Y., Wu, Q., Zhang, L., Wang, Q., Yang, Z.-X., Liu, J., & Feng, L. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.104538 · Cited by 139
Adaptor protein complexes and disease at a glance
Sanger, A., Hirst, J., Davies, A. K., & Robinson, M. S. (2019) · Journal of Cell Science · doi:10.1242/jcs.222992 · Cited by 135
“Defective autophagy is implicated in the aetiology of many neurodegenerative diseases (Menzies et al., 2017) and neuronal-specific loss of Atg9a in mice causes severe neurological phenotypes (Yamaguchi et al., 2018).”
BackgroundNiewiadomska, G., Niewiadomski, W., Steczkowska, M., & Gąsiorowska, A. (2021) · Life · doi:10.3390/life11010028 · Cited by 138
Behl, T., Makkar, R., Sehgal, A., Singh, S., Sharma, N., Zengin, G., BUNGAU, S. G., Andronie-Cioară, F. L., Munteanu, M. A., Brisc, M. C., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22147432 · Cited by 134
“neuronal cell death in diseases, such as protein homeostasis, [20] mitochondrial dysfunc-”
BackgroundInfluentialThe protective role of exercise against age-related neurodegeneration
Sujkowski, A. L., Hong, L., Wessells, R. J., & Todi, S. V. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101543 · Cited by 142
Autophagy Dysfunction in Alzheimer’s Disease: Mechanistic Insights and New Therapeutic Opportunities
Di Meco, A., Curtis, M. E., Lauretti, E., & Praticò, D. (2020) · Biological Psychiatry · doi:10.1016/j.biopsych.2019.05.008 · Cited by 133
Parkinson's disease: convergence on synaptic homeostasis
Soukup, S., Vanhauwaert, R., & Verstreken, P. (2018) · The EMBO Journal · doi:10.15252/embj.201898960 · Cited by 131
“Following elongation and maturation, the autophagosome fuses with the lysosome, a process mediated by SNAREs (soluble N-ethylmaleimide-sensitive factor activating protein receptors; Menzies et al, 2017).”
MethodMicroglial-to-neuronal CCR5 signaling regulates autophagy in neurodegeneration
Festa, B. P., Siddiqi, F. H., Jimenez-Sanchez, M., Won, H., Rob, M., Djajadikerta, A., Stamatakou, E., & Rubinsztein, D. C. (2023) · Neuron · doi:10.1016/j.neuron.2023.04.006 · Cited by 129
“Furthermore, genetic or pharmacological induction of autophagy enhances the clearance of aggregate-prone proteins and attenuates deleterious phenotypes observed in animal models mimicking these disorders.(3,4)”
BackgroundSelf-citationFelodipine induces autophagy in mouse brains with pharmacokinetics amenable to repurposing
Siddiqi, F. H., Menzies, F. M., López, A., Stamatakou, E., Karabiyik, C., Ureshino, R. P., Ricketts, T., Jiménez-Sánchez, M., Esteban, M. A., Lai, L., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09494-2 · Cited by 134
Self-citationFedeli, C., Filadi, R., Rossi, A., Mammucari, C., & Pizzo, P. (2019) · Autophagy · doi:10.1080/15548627.2019.1596489 · Cited by 134
“formation of both protein aggregates [1,3].”
BackgroundGlycogen Synthase Kinase-3 Inhibitors: Preclinical and Clinical Focus on CNS-A Decade Onward
Ruiz, S. M. A., & Eldar-Finkelman, H. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.792364 · Cited by 133
“From a mechanistic point of view, inhibition GSK-3 may reduce mHtt toxicity via the ability to increase the amount of heat shock proteins [activation of heat shock factor-1 (HSF1)], by activating autophagy, and by reducing tau pathology (Carmichael et al., 2002; L’Episcopo et al., 2016; Menzies et al., 2017; Rippin et…”
BackgroundRusso, R., Varano, G. P., Adornetto, A., Nazio, F., Tettamanti, G., Girardello, R., Cianfanelli, V., Cavaliere, F., Morrone, L. A., Corasaniti, M. T., et al. (2018) · Cell Death and Disease · doi:10.1038/s41419-018-1044-5 · Cited by 125
Acyl-CoA-Binding Protein Is a Lipogenic Factor that Triggers Food Intake and Obesity
Pedro, J. M. B., Sica, V., Martins, I., Pol, J. G., Loos, F., Maiuri, M. C., Durand, S., Bossut, N., Aprahamian, F., Anagnostopoulos, G., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.07.010 · Cited by 127
Neurodegeneration and Neuro-Regeneration—Alzheimer’s Disease and Stem Cell Therapy
Vasić, V., Barth, K., & Schmidt, M. H. H. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20174272 · Cited by 129
“a link between the expression of several autophagy genes and AD [102,103].”
BackgroundAutophagy in health and disease: From molecular mechanisms to therapeutic target
Lu, G. X., Wang, Y., Shi, Y. P., Zhang, Z., Huang, C., He, W., Wang, C., & Shen, H. (2022) · MedComm · doi:10.1002/mco2.150 · Cited by 135
Metadata
- Authors
- Menzies, F. M., Fleming, A., Caricasole, A., Bento, C. F., Andrews, S. P., Ashkenazi, A., Füllgrabe, J., Jackson, A., Jimenez Sanchez, M., Karabiyik, C., Licitra, F., Lopez Ramirez, A., Pavel, M., Puri, C., Renna, M., Ricketts, T., Schlotawa, L., Vicinanza, M., Won, H., Zhu, Y., Skidmore, J., & Rubinsztein, D. C.
- Affiliations
- University of Cambridge (GB)
- Corresponding author
- Rubinsztein, David C.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2017-03
- Volume
- 93
- Issue
- 5
- Pages
- 1015-1034
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2592067246
- Cited by
- 1,134
- References
- 288
- Citations by year
- 2026: 68 · 2025: 96 · 2024: 107 · 2023: 119 · 2022: 153 · 2021: 138 · 2020: 145 · 2019: 159 · 2018: 108 · 2017: 39
- FWCI
- 16.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (acceptedVersion, other-oa)
- Research Portal (King's College London) (submittedVersion, other-oa)
- Apollo (University of Cambridge) (submittedVersion, cc-by-nc-nd)
- Apollo
- Funders
- Tau Consortium
- Alzheimer’s Research UK
- Wellcome Trust (095317/Z/11/Z)
- Cambridge Institute for Medical Research (100140/Z/12/Z)
- NIHR Biomedical Research Unit in Dementia at Addenbrooke’s Hospital
- The Rosetrees Trust
- FEBS
- Addenbrooke’s Charitable Trust
- Sims Scholarship
- James Baird Fund
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- autophagy, neurodegeneration, lysosomal degradation, protein aggregation, neurodegenerative diseases, therapeutic target, druggable targets, mouse knockout models
- MeSH terms
- Animals, Autophagy, Humans, Lysosomes, Motor Neurons, Proteins, Signal Transduction, Neurodegenerative Diseases
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