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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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Iron Overload Impairs Autophagy: Effects of Rapamycin in Ameliorating Iron-Related Memory Deficits
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“The entire process is regulated by a series of autophagy-related (ATG) proteins; further details extend beyond the scope of the present article but have been described in recent reviews extensively [29].”
BackgroundSenescent AECⅡ and the implication for idiopathic pulmonary fibrosis treatment
Zhang, T., Zhang, J., Lv, C., Li, H., & Song, X. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1059434 · Cited by 25
“torin-1, PP242h) and the direct activators of AMPK (metformin and alginate), as well as the regulators of the acetylation pathway (spermidine and resveratrol), and also classical autophagyinducing factors such as transcription factor EB (TFEB) (Rubinsztein et al., 2012; Menzies et al., 2017; Aman et al., 2021).”
BackgroundThe active zone protein Clarinet regulates synaptic sorting of ATG-9 and presynaptic autophagy
Zhao, X., Yang, S., Kargbo-Hill, S. E., Clark, B., Manning, L., & Colón‐Ramos, D. A. (2023) · PLoS Biology · doi:10.1371/journal.pbio.3002030 · Cited by 26
The In Vitro Effects of Enzymatic Digested Gliadin on the Functionality of the Autophagy Process
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“As already stated, this process plays a crucial role in several physiological and pathological mechanisms, such as protein aggregates degradation [32,33].”
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“As many different pathomechanisms may lead to neurodegeneration, various disease-specific deregulations of the autophagic pathway have been suggested [81, 97].”
BackgroundDrosophila Atg9 regulates the actin cytoskeleton via interactions with profilin and Ena
Kiss, V., Jipa, A., Varga, K., Takáts, S., Maruzs, T., Lőrincz, P., Simon‐Vecsei, Z., Szikora, S., Földi, I., Bajusz, C., et al. (2019) · Cell Death and Differentiation · doi:10.1038/s41418-019-0452-0 · Cited by 26
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“Normally, aggregate‐prone proteins, including Aβ, are removed by autophagy [97].”
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Intermittent fasting in health and disease
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“Mutations in genes like PARK7, α -synuclein, parkin, PINK1 , and LRRK2 lead to mitochondrial dysfunction, contributing to PD [7]. α -synuclein mutations cause protein aggregation, disrupting mitophagy, while PINK1 deletion increases oxidative stress in mitochondria [38].”
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“5,13 Growing evidence suggests that autophagy dysfunction may occur even prior to the deposition of A β plaques, highlighting its potential role in the early stages of the disease.”
Regulation of Inositol Biosynthesis: Balancing Health and Pathophysiology
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Pathogenic Single Nucleotide Polymorphisms on Autophagy-Related Genes
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“Undoubtedly, one of the clinical contexts in which the link between deficient autophagy and pathology is more firmly-established is neurodegeneration [35].”
BackgroundViral Bcl2s’ transmembrane domain interact with host Bcl2 proteins to control cellular apoptosis
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“In addition, increased autophagy has been suggested to reduce Aβ levels (57).”
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“It is found that deficiency of autophagy contributes to AD pathogenesis, and upregulation of the autophagic level is recorded as a promising strategy for the improvement of AD (Menzies et al. 2017; Zhang, Yang, et al. 2021).”
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“Additionally, several NCL disease models display aberrant autophagy, which has also been reported in other forms of neurodegeneration [110].”
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“Autophagy impairment has been reported in several pathologies, from neurodegeneration to cancer [67,68].”
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“In fact, defects in autophagy have been implicated in neurological disease such as Parkinson’s and Alzheimer’s [13,14].”
BackgroundEpigenetic regulation in the pathophysiology of Lewy body dementia
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SSH1 impedes SQSTM1/p62 flux and MAPT/Tau clearance independent of CFL (cofilin) activation
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Vinexin contributes to autophagic decline in brain ageing across species
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“Consistent with this observation, dysfunctional autophagy is implicated in common, age-related neurodegenerative conditions such as Alzheimer’s disease and Parkinson’s disease [8].”
BackgroundSelf-citationRecent developments of neuroprotective agents for degenerative retinal disorders
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Autophagy protein ULK1 interacts with and regulates SARM1 during axonal injury
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“On the other hand, autophagic flux is required for neuronal survival under both homeostatic and stress conditions by eliminating toxic protein aggregates and dysfunctional organelles (44, 45, 49, 50).”
BackgroundLysosomal genes contribute to Parkinson’s disease near agriculture with high intensity pesticide use
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“Dysfunction of autophagy has also been implicated in other neurodegenerative diseases such as Alzheimer ’ s disease 35 , and the added toxicity from pesticide exposure coupled with a potent genetic variant affecting autophagy might very well cause a Parkinsonian disorder.”
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“dystrophy, and often associated with the build up of toxic intra- and extra-cellular protein aggregates (reviewed in [1]).”
BackgroundInfluentialE46K Mutant α-Synuclein Is Degraded by Both Proteasome and Macroautophagy Pathway
Yan, J., Yuan, Y., Chu, S., Li, G., & Chen, N. (2018) · Molecules · doi:10.3390/molecules23112839 · Cited by 23
Orientin Improves Cognition by Enhancing Autophagosome Clearance in an Alzheimer’s Mouse Model
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“Diminished or loss of autophagic activity contributes to aging and plays a key role in the onset of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), and related neurodegenerative pathologies [14].”
Focus on the Multimodal Role of Autophagy in Rheumatoid Arthritis
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“We and other previous studies (Lim et al., 2011; Miyara et al., 2016) demonstrated that mild MPP+ exposure predominantly inhibited impaired autophagosome degradation in MN9D cells (Supplementary Figure 3).”
BackgroundResultNeuroprotective properties of queen bee acid by autophagy induction
Martínez-Chacón, G., Paredes-Barquero, M., Yakhine-Diop, S. M. S., Uribe-Carretero, E., Bargiela, A., Sabater-Arcis, M., Morales-Garcia, J. A., Alarcón-Gil, J., Alegre-Cortés, E., Canales-Cortés, S., et al. (2021) · Cell Biology and Toxicology · doi:10.1007/s10565-021-09625-w · Cited by 22
“Accumulated evidence has revealed that autophagy is essential for the healthy aging of neurons (Menzies et al. 2017; Rubinsztein et al. 2012).”
BackgroundProlyl oligopeptidase acts as a link between chaperone-mediated autophagy and macroautophagy
Cui, H., Norrbacka, S., & Myöhänen, T. T. (2021) · Biochemical Pharmacology · doi:10.1016/j.bcp.2021.114899 · Cited by 21
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“Normal autophagy was considered as a protective factor against neurodegeneration, infection, and brain injury disease [51]; however, autophagy dysfunction was associated with increased susceptibility of neurons to ischemic injury.”
BackgroundLRRK2 and Proteostasis in Parkinson’s Disease
Pérez‐Carrión, M. D., Posadas, I., Solera, J., & Ceña, V. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23126808 · Cited by 23
Loss of TMEM106B exacerbates Tau pathology and neurodegeneration in PS19 mice
Feng, T., Du, H., Yang, C., Wang, Y., & Hu, F. (2024) · Acta Neuropathologica · doi:10.1007/s00401-024-02702-4 · Cited by 22
“It has been demonstrated that phosphorylated Tau and Tau aggregates are degraded by the autophagy-lys-osomal pathway [42, 50, 61, 95] and hyperphosphoryl-ated Tau co-localizes with the autophagosome markers LC3 and p62 proteins in human patients with tauopathy [73].”
Zhang, J., Jiang, Y., Dong, X., Meng, Z., Ji, L., Kang, Y., Liu, M., Zhou, W., & Song, W. (2024) · Alzheimer s Research & Therapy · doi:10.1186/s13195-024-01527-3 · Cited by 23
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Self-citationCLEC16A regulates splenocyte and NK cell function in part through MEK signaling
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Targeting Histone Demethylase LSD1/KDM1a in Neurodegenerative Diseases
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Biological Modulation of Autophagy by Nanoplastics: A Current Overview
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“It facilitates the clearance of damaged mitochondria and aggregated proteins, thereby preserving synaptic function and neuroplasticity [95].”
HERC1 Ubiquitin Ligase Is Required for Hippocampal Learning and Memory
Pérez-Villegas, E. M., Pérez-Rodríguez, M., Negrete‐Díaz, J. V., Ruiz, R., Rosa, J. L., de Toledo, G. Á., Moreno, A. R., & Armengol, J. A. (2020) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2020.592797 · Cited by 21
“The E3 ligases in the UPS have been implicated in the maintenance of spine size, density and number, through regulation of AMPA receptor expression, or of NMDA receptor and RhoA activity (Hamilton and Zito, 2013; Mertz et al., 2015; Hamilton et al., 2017).”
BackgroundXu, H., Zhu, Y., Chen, X., Yang, T., Wang, X., Xu, S., Xie, X., Hu, M., Jiang, L., Cheng, J., et al. (2021) · Archives of Toxicology · doi:10.1007/s00204-021-03131-y · Cited by 20
Self-citationPropofol protects hippocampal neurons in sleep-deprived rats by inhibiting mitophagy and autophagy
Dai, W., Xiao, Y., Tu, Y., Xiao, F., Lu, Y., Qin, Y., & Xie, Y. (2021) · Annals of Translational Medicine · doi:10.21037/atm-21-3872 · Cited by 20
“purpose of autophagy activation is to adjust intracytoplasmic components and to regulate energy metabolism and maintain cellular homeostasis to promote cell survival (7).”
BackgroundKim, Y., Park, S., Lee, J., Jang, J., Jung, J., Koh, J., Choi, C. S., Wolfe, R. R., & Kim, I. (2022) · Metabolites · doi:10.3390/metabo12010084 · Cited by 20
“Previous studies have shown that the autophagy pathway can be enhanced to regulate protein quality through facilitating degradation of the aggregated pathogenic protein [53,54].”
BackgroundNutritional strategies for autophagy activation and health consequences of autophagy impairment
Kocot, A. M., & Wróblewska, B. (2022) · Nutrition · doi:10.1016/j.nut.2022.111686 · Cited by 22
Wu, J., Wang, L., Ervin, J. F., Wang, S. J., Soderblom, E. J., Ko, D. C., & Yan, D. (2022) · Science Advances · doi:10.1126/sciadv.adc9236 · Cited by 17
“The aging phenotypes of these neurons are well characterized: PLM neuron processes exhibit wavy and acute bends (28); PVD displayed bead structures along neuronal processes that are enriched with autophagosomes and fragmented microtubules (27, 32), which is reminiscent of descriptions of mammalian neurons in neurodege…”
BackgroundZhang, S., Cao, F., Li, W., & Abumaria, N. (2023) · Science Signaling · doi:10.1126/scisignal.ade6325 · Cited by 20
García‐Juan, M., Ordóñez‐Gutiérrez, L., & Wandosell, F. G. (2023) · Glia · doi:10.1002/glia.24492 · Cited by 21
“The imbalance of autophagy is especially relevant in many neuro-degenerative diseases and has shown an impact in the clearance of protein aggregates in neurons (Frake et al., 2015; Menzies et al., 2017; Qaisiya et al., 2017; Sarkar et al., 2007; Webb et al., 2003; Yamamoto & Simonsen, 2011).”
BackgroundSeranova, E., Palhegyi, A. M., Verma, S., Dimova, S., Lasry, R., Naama, M., Sun, C., Barrett, T. G., Rosenstock, T. R., Kumar, D., et al. (2020) · Journal of Molecular Biology · doi:10.1016/j.jmb.2020.01.024 · Cited by 20
“Many of these pathologies occurring due to abnormal accumulation of undesirable macromolecules are broadly classified under macromolecule storage disorders, which encompass several neurodegenerative and lysosomal storage disorders [7,104,105].”
InfluentialAlexander-Floyd, J., Haroon, S., Ying, M., Entezari, A. A., Jaeger, C., Vermulst, M., & Gidalevitz, T. (2020) · BMC Biology · doi:10.1186/s12915-020-0750-5 · Cited by 19
Visualization of Autophagy Progression by a Red–Green–Blue Autophagy Sensor
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Development of a specific live-cell assay for native autophagic flux
Safren, N., Tank, E. M. H., Malik, A. M., Chua, J. P., Santoro, N., & Barmada, S. J. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101003 · Cited by 18
“Defective autophagy is a common feature of many neurodegenerative diseases including Alzheimer’s disease (17, 18), Parkinson’s disease (19–23), polyglutamine disorders (24–26), amyotrophic lateral sclerosis (ALS) (27), and frontotemporal dementia (FTD) (28–31).”
BackgroundMarín, T., Dulcey, A. E., Campos, F., de la Fuente, C., Acuña, M., Castro, J., Pinto, C., Yañez, M. J., Cortéz, C., McGrath, D. W., et al. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.844297 · Cited by 20
“Neurons are particularly affected by disruptions of autophagy which are associated with many neurodegenerative disorders (Nixon, 2013; Lee et al., 2016; Menzies et al., 2017).”
InfluentialXu, Z., Nan, W., Zhang, X., Sun, Y., Yang, J., Lu, K., Liu, Y., Gao, Y., Yang, F., Mao, W., et al. (2018) · Journal of Molecular Neuroscience · doi:10.1007/s12031-018-1075-5 · Cited by 19
The HERC1 ubiquitin ligase regulates presynaptic membrane dynamics of central synapses
Montes-Fernández, M. A., Pérez-Villegas, E. M., García-Gonzalo, F. R., Pedrazza, L., Rosa, J. L., de Toledo, G. Á., & Armengol, J. A. (2020) · Scientific Reports · doi:10.1038/s41598-020-68970-8 · Cited by 20
Respiratory pathology in the Optn mouse model of Amyotrophic Lateral Sclerosis
McCall, A. L., Dhindsa, J. S., Pucci, L. A., Kahn, A. F., Fusco, A. F., Biswas, D. D., Strickland, L. M., Tseng, H. C., & ElMallah, M. K. (2020) · Respiratory Physiology & Neurobiology · doi:10.1016/j.resp.2020.103525 · Cited by 19
Naseer, A., Mir, S. S., Takács‐Vellai, K., & Nazir, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222212263 · Cited by 22
“elegans uncoordinated-51 kinase) to stimulate the formation of complexes containing ATG13, FIP200 (focal adhesion kinase family-interacting protein of 200 kDa) and ATG101, which further mediate autophagosome formation, leading to the initiation of autophagy [25] (Figure 1).”
BackgroundInfluentialAge-related neuronal damage by advanced glycation end products through altered proteostasis
Addi, U. R., Jakhotia, S., Reddy, S. S., & Reddy, G. B. (2022) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2022.109840 · Cited by 19
A review of autophagy mechanism of statins in the potential therapy of Alzheimer’s disease
Liu, L., Dai, W.-Z., Zhu, X., & Ma, T. (2022) · Journal of Integrative Neuroscience · doi:10.31083/j.jin2102046 · Cited by 20
Protective role of autophagy in triptolide-induced apoptosis of TM3 Leydig cells
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Rnd3 Expression is Necessary to Maintain Mitochondrial Homeostasis but Dispensable for Autophagy
Cueto‐Ureña, C., Mocholí, E., Escrivá-Fernández, J., González-Granero, S., Sánchez-Hernández, S., Solana-Orts, A., Ballester‐Lurbe, B., Benabdellah, K., Guasch, R. M., García‐Verdugo, J. M., et al. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.834561 · Cited by 17
The autophagy inducer SMER28 attenuates microtubule dynamics mediating neuroprotection
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Rooney, T. P. C., Aldred, G. G., Boffey, H. K., Willems, H. M. G., Edwards, S. J., Chawner, S. J., Scott, D. E., Green, C., Winpenny, D., Skidmore, J., et al. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01693 · Cited by 19
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“Autophagy is a critical process in a multicellular organism during embryogenesis, and in aging, and also plays a role in the development of diseases, including heart failure [41], myopathies [42] and neurodegenerative diseases [43].”
BackgroundExcessive STAU1 condensate drives mTOR translation and autophagy dysfunction in neurodegeneration
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Autophagy regulator ATG5 preserves cerebellar function by safeguarding its glycolytic activity
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Protective Effects of Flavonoid Rutin Against Aminochrome Neurotoxicity
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“42,43 In a similar manner to the UPS system, autophagy utilizes Ub as a tag for degradation.”
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Self-citationAlzheimer’s disease: an axonal injury disease?
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“Autophagy defects rather than excessive autophagy induction have been associated with axonal and dendritic dystrophy, leading to the loss of synaptic integrity in various neurodegenerative conditions (Frake et al., 2015; Menzies et al., 2017).”
Dual Implications of Nanosilver-Induced Autophagy: Nanotoxicity and Anti-Cancer Effects
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“As outlined above, the inability of the cell to properly regulate autophagy is associated with aging and is also implicated in the pathogenesis of various disorders, such as neurodegenerative diseases, type 2 diabetes, Crohn’s disease, and cancer [19,20,27].”
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“58 p62 is an autophagy degradation substrate.”
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Self-citationCongenital Disorders of Autophagy: What a Pediatric Neurologist Should Know
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Autophagy in the mammalian nervous system: a primer for neuroscientists
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Ramadan fasting during Covid-19 pandemic
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“[25] By means of the aforementioned mechanisms, fasting can also alleviate symptoms of asthma, multiple sclerosis, and arthritis.”
BackgroundAutophagy in axonal and presynaptic development
Crawley, O., & Grill, B. J. (2021) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2021.03.011 · Cited by 17
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Digest it all: the lysosomal turnover of cytoplasmic aggregates
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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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