A small-molecule scaffold induces autophagy in primary neurons and protects against toxicity in a Huntington disease model
Open accessAbstract
Autophagy is an intracellular turnover pathway. It has special relevance for neurodegenerative proteinopathies, such as Alzheimer disease, Parkinson disease, and Huntington disease (HD), which are characterized by the accumulation of misfolded proteins. Although induction of autophagy enhances clearance of misfolded protein and has therefore been suggested as a therapy for proteinopathies, neurons appear to be less responsive to classic autophagy inducers than nonneuronal cells. Searching for improved inducers of neuronal autophagy, we discovered an N 10 -substituted phenoxazine that, at proper doses, potently and safely up-regulated autophagy in neurons in an Akt- and mTOR-independent fashion. In a neuron model of HD, this compound was neuroprotective and decreased the accumulation of diffuse and aggregated misfolded protein. A structure/activity analysis with structurally similar compounds approved by the US Food and Drug Administration revealed a defined pharmacophore for inducing neuronal autophagy. This pharmacophore should prove useful in studying autophagy in neurons and in developing therapies for neurodegenerative proteinopathies.
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Selective MTORC1 inhibition via everolimus or modulation of MTOR- and AKT-independent pathways with 10-NCP are more successful in neurons.
“Alternative methods have proven more successful in neurons, however, including selective MTORC1 inhibition via everolimus [385–387], or modulation of MTOR- and AKT-independent pathways with 10-NCP, an N10-substituted derivative of the heterocyclic dye compound and antipsychotic analog phenoxazine [384].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [384]
Rapamycin and related MTOR inhibitors, as well as AKT inhibitors, are ineffective inducers of neuronal autophagy.
“rapamycin and related MTOR inhibitors, as well as AKT inhibitors, are ineffective inducers of neuronal autophagy [338,384].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [384]
10-NCP and related compounds are capable of inducing neuronal autophagy through an MTOR- and AKT-independent signaling cascade.
“10-NCP and related compounds are also capable of inducing neuronal autophagy through an MTOR- and AKT-independent signaling cascade [357,384].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [384]
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Cites
Autophagy fights disease through cellular self-digestion
Mizushima, N., Levine, B., Cuervo, A. M., & Klionsky, D. J. (2008) · Nature · doi:10.1038/nature06639 · Cited by 6,452 · see citing works
Methods in Mammalian Autophagy Research
Mizushima, N., Yoshimori, T., & Levine, B. (2010) · Cell · doi:10.1016/j.cell.2010.01.028 · Cited by 4,497 · see citing works
Loss of autophagy in the central nervous system causes neurodegeneration in mice
Komatsu, M., Waguri, S., Chiba, T., Murata, S., Iwata, J.-I., Tanida, I., Ueno, T., Koike, M., Uchiyama, Y., Kominami, E., et al. (2006) · Nature · doi:10.1038/nature04723 · Cited by 3,500 · see citing works
Mangiarini, L., Sathasivam, K., Seller, M., Cozens, B., Harper, A., Hetherington, C., Lawton, M., Trottier, Y., Lehrach, H., Davies, S. W., et al. (1996) · Cell · doi:10.1016/s0092-8674(00)81369-0 · Cited by 3,073 · see citing works
Ravikumar, B., Vacher, C., Berger, Z., Davies, J. E., Luo, S., Oroz, L. G., Scaravilli, F., Easton, D. F., Duden, R., O'Kane, C. J., et al. (2004) · Nature Genetics · doi:10.1038/ng1362 · Cited by 2,347 · see citing works
Mizushima, N., Yamamoto, A., Matsui, M., Yoshimori, T., & Ohsumi, Y. (2003) · Molecular Biology of the Cell · doi:10.1091/mbc.e03-09-0704 · Cited by 2,323 · see citing works
Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes
Klionsky, D. J., Abeliovich, H., Agostinis, P., Agrawal, D. K., Aliev, G., Askew, D. S., Baba, M., Baehrecke, E. H., Bahr, B. A., Ballabio, A., et al. (2008) · Autophagy · doi:10.4161/auto.5338 · Cited by 2,230 · see citing works
Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death
Arrasate, M., Mitra, S., Schweitzer, E. S., Segal, M. R., & Finkbeiner, S. (2004) · Nature · doi:10.1038/nature02998 · Cited by 1,979 · see citing works
Self-citationα-Synuclein Is Degraded by Both Autophagy and the Proteasome
Webb, J. L., Ravikumar, B., Atkins, J., Skepper, J. N., & Rubinsztein, D. C. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300227200 · Cited by 1,429 · see citing works
Yamamoto, A., Tagawa, Y., Yoshimori, T., Moriyama, Y., Masaki, R., & Tashiro, Y. (1998) · Cell Structure and Function · doi:10.1247/csf.23.33 · Cited by 1,312 · see citing works
Hypothalamic mTOR Signaling Regulates Food Intake
Cota, D., Proulx, K., Smith, K. A. B., Kozma, S. C., Thomas, G., Woods, S. C., & Seeley, R. J. (2006) · Science · doi:10.1126/science.1124147 · Cited by 1,278 · see citing works
Boland, B., Kumar, A., Lee, S., Platt, F. M., Wegiel, J., Yu, W. H., & Nixon, R. A. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.0800-08.2008 · Cited by 1,119 · see citing works
Potential therapeutic applications of autophagy
Rubinsztein, D. C., Gestwicki, J. E., Murphy, L. O., & Klionsky, D. J. (2007) · Nature Reviews Drug Discovery · doi:10.1038/nrd2272 · Cited by 1,004 · see citing works
Novel targets for Huntington's disease in an mTOR-independent autophagy pathway
Williams, A., Sarkar, S., Cuddon, P., Ttofi, E. K., Saiki, S., Siddiqi, F. H., Jahreiss, L., Fleming, A., Pask, D., Goldsmith, P., et al. (2008) · Nature Chemical Biology · doi:10.1038/nchembio.79 · Cited by 800 · see citing works
Autophagy, amyloidogenesis and Alzheimer disease
Nixon, R. A. (2007) · Journal of Cell Science · doi:10.1242/jcs.019265 · Cited by 749 · see citing works
Small molecules enhance autophagy and reduce toxicity in Huntington's disease models
Sarkar, S., Perlstein, E. O., Imarisio, S., Pineau, S., Cordenier, A., Maglathlin, R. L., Webster, J. A., Lewis, T. A., O’Kane, C. J., Schreiber, S. L., et al. (2007) · Nature Chemical Biology · doi:10.1038/nchembio883 · Cited by 596 · see citing works
Induction of Autophagy during Extracellular Matrix Detachment Promotes Cell Survival
Fung, C., Lock, R., Gao, S., Salas, E., & Debnath, J. (2008) · Molecular Biology of the Cell · doi:10.1091/mbc.e07-10-1092 · Cited by 558 · cited 14× · see citing works
“16982–16987 | PNAS | September 28, 2010 | vol. 107 | no. 39 www.pnas.org/cgi/doi/10.1073/pnas.1004498107 If 10-NCP increases LC3-II levels by promoting autophagy, it should induce formation of GFP-LC3-positive autophagosomes in GFP-LC3 transgenic neurons (15).”
BackgroundMethodInfluentialLithium delays progression of amyotrophic lateral sclerosis
Fornai, F., Longone, P., Cafaro, L., Kastsiuchenka, O., Ferrucci, M., Manca, M. L., Lazzeri, G., Spalloni, A., Bellio, N., Lenzi, P., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0708022105 · Cited by 550 · see citing works
Small molecule regulators of autophagy identified by an image-based high-throughput screen
Zhang, L., Yu, J., Pan, H., Hu, P., Yan, H., Cai, W., Zhu, H., Yu, A. D., Xie, X., Ma, D., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0709695104 · Cited by 470 · see citing works
Barnett, S. F., Defeo-Jones, D., Fu, S., Hancock, P. J., Haskell, K., Jones, R. E., Kahana, J. A., Kral, A. M., Leander, K. R., LEE, L. L., et al. (2005) · Biochemical Journal · doi:10.1042/bj20041140 · Cited by 398 · see citing works
Identification of Common Functional Configurations Among Molecules
Barnum, D., Greene, J. W., Smellie, A. S., & Sprague, P. W. (1996) · Journal of Chemical Information and Computer Sciences · doi:10.1021/ci950273r · Cited by 319 · see citing works
AMPA receptors regulate transcription of the plasticity-related immediate-early gene Arc
Rao, V. R., Pintchovski, S. A., Chin, J., Peebles, C., Mitra, S. S., & Finkbeiner, S. M. (2006) · Nature Neuroscience · doi:10.1038/nn1708 · Cited by 188 · see citing works
Self-citationBiogenesis of Multilamellar Bodies via Autophagy
Hariri, M., Millane, G., Guimond, M.-P., Guay, G., Dennis, J. W., & Nabi, I. R. (2000) · Molecular Biology of the Cell · doi:10.1091/mbc.11.1.255 · Cited by 188 · see citing works
The cellular pathways of neuronal autophagy and their implication in neurodegenerative diseases
Yue, Z., Friedman, L. G., Komatsu, M., & Tanaka, K. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2009.01.016 · Cited by 173 · see citing works
Automated microscope system for determining factors that predict neuronal fate
Arrasate, M., & Finkbeiner, S. M. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0409777102 · Cited by 130 · see citing works
Self-citationFengsrud, M., Roos, N., Berg, T., Liou, W., Slot, J. W., & Seglen, P. O. (1995) · Experimental Cell Research · doi:10.1006/excr.1995.1402 · Cited by 122 · see citing works
King, M. A., Hands, S., Hafiz, F., Mizushima, N., Tolkovsky, A. M., & Wyttenbach, A. (2008) · Molecular Pharmacology · doi:10.1124/mol.107.043398 · Cited by 120 · see citing works
Mitra, S. S., Tsvetkov, A. S., & Finkbeiner, S. M. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m806269200 · Cited by 106 · see citing works
Self-citationIdentification of N10-Substituted Phenoxazines as Potent and Specific Inhibitors of Akt Signaling
Thimmaiah, K. N., Easton, J. B., Germain, G. S., Morton, C. L., Kamath, S., Buolamwini, J. K., & Houghton, P. J. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m507057200 · Cited by 99 · see citing works
Fox, J. H., Connor, T., Chopra, V., Dorsey, K., Kama, J. A., Bleckmann, D., Betschart, C., Hoyer, D., Frentzel, S., DiFiglia, M., et al. (2010) · Molecular Neurodegeneration · doi:10.1186/1750-1326-5-26 · Cited by 94 · see citing works
Splice Variants of the NR1 Subunit Differentially Induce NMDA Receptor-Dependent Gene Expression
Bradley, J., Carter, S. R., Rao, V. R., Wang, J., & Finkbeiner, S. M. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.3347-05.2006 · Cited by 69 · see citing works
Self-citationProtein turnover and inclusion body formation
Mitra, S. S., Tsvetkov, A. S., & Finkbeiner, S. M. (2009) · Autophagy · doi:10.4161/auto.5.7.9291 · Cited by 65 · see citing works
Self-citationAmelioration of protein misfolding disease by rapamycin: Translation or autophagy?
Wyttenbach, A., Hands, S. L., King, M. A., Lipkow, K., & Tolkovsky, A. M. (2008) · Autophagy · doi:10.4161/auto.6059 · Cited by 37 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).
Klionsky, D. J., Abdelmohsen, K., Abe, A., Abedin, M. J., Abeliovich, H., Acevedo Arozena, A., Adachi, H., Adams, C. M., Adams, P. D., Adeli, K., et al. (2016) · Autophagy · doi:10.1080/15548627.2015.1100356 · Cited by 5,894 · see citing works
Self-citationGuidelines for the use and interpretation of assays for monitoring autophagy
Klionsky, D. J., Abdalla, F. C., Abeliovich, H., Abraham, R. T., Acevedo-Arozena, A., Adeli, K., Agholme, L., Agnello, M., Agostinis, P., Aguirre-Ghiso, J. A., et al. (2012) · Autophagy · doi:10.4161/auto.19496 · Cited by 3,996 · see citing works
Self-citationKlionsky, D. J., Abdel-Aziz, A. K., Abdelfatah, S., Abdellatif, M., Abdoli, A., Abel, S., Abeliovich, H., Abildgaard, M. H., Abudu, Y. P., Acevedo-Arozena, A., et al. (2021) · Autophagy · doi:10.1080/15548627.2020.1797280 · Cited by 2,622 · see citing works
Self-citationThe Biology of Proteostasis in Aging and Disease
Labbadia, J., & Morimoto, R. I. (2015) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-060614-033955 · Cited by 1,472 · see citing works
Heras-Sandoval, D., Pérez-Rojas, J. M., Hernández-Damián, J., & Pedraza-Chaverri, J. (2014) · Cellular Signalling · doi:10.1016/j.cellsig.2014.08.019 · Cited by 1,091 · see citing works
Autophagy induction enhances TDP43 turnover and survival in neuronal ALS models
Barmada, S. J., Serio, A., Arjun, A., Bilican, B., Daub, A., Ando, D. M., Tsvetkov, A., Pleiss, M., Li, X., Peisach, D., et al. (2014) · Nature Chemical Biology · doi:10.1038/nchembio.1563 · Cited by 431 · see citing works
Self-citationCompartment-Specific Regulation of Autophagy in Primary Neurons
Maday, S., & Holzbaur, E. L. F. (2016) · The Journal of Neuroscience · doi:10.1523/jneurosci.4401-15.2016 · Cited by 309 · see citing works
Congdon, E. E., Wu, J. W., Myeku, N., Figueroa, Y. H., Herman, M., Marinec, P. S., Gestwicki, J. E., Dickey, C. A., Yu, W. H., & Duff, K. E. (2012) · Autophagy · doi:10.4161/auto.19048 · Cited by 297 · see citing works
Deconstruction for Reconstruction: The Role of Proteolysis in Neural Plasticity and Disease
Bingol, B., & Sheng, M. (2011) · Neuron · doi:10.1016/j.neuron.2010.11.006 · Cited by 275 · see citing works
Mechanisms of selective autophagy and mitophagy: Implications for neurodegenerative diseases
Chu, C. T. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.07.015 · Cited by 218 · see citing works
Autophagy and Its Normal and Pathogenic States in the Brain
Yamamoto, A., & Yue, Z. (2014) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-071013-014149 · Cited by 204 · see citing works
The Autophagy Lysosomal Pathway and Neurodegeneration
Finkbeiner, S. (2020) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a033993 · Cited by 196 · see citing works
Self-citationAutophagy and ALS: mechanistic insights and therapeutic implications
Chua, J. P., De Calbiac, H., Kabashi, E., & Barmada, S. J. (2022) · Autophagy · doi:10.1080/15548627.2021.1926656 · Cited by 189 · see citing works
“ods have proven more successful in neurons, however, including selective MTORC1 inhibition via everolimus [385–387], or modulation of MTOR- and AKT-independent pathways with 10-NCP, an N(10)-substituted derivative of the heterocyclic dye compound and antipsychotic analog phenoxazine [384].”
BackgroundTashiro, Y., Urushitani, M., Inoue, H., Koike, M., Uchiyama, Y., Komatsu, M., Tanaka, K., Yamazaki, M., Abe, M., Misawa, H., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.417600 · Cited by 194 · see citing works
ATP13A2 regulates mitochondrial bioenergetics through macroautophagy
Gusdon, A. M., Zhu, J., Van Houten, B., & Chu, C. T. (2012) · Neurobiology of Disease · doi:10.1016/j.nbd.2011.12.015 · Cited by 167 · see citing works
Degradation of tau protein by autophagy and proteasomal pathways
Wang, Y., & Mandelkow, E. (2012) · Biochemical Society Transactions · doi:10.1042/bst20120071 · Cited by 166 · see citing works
Hung, C. O. Y., & Livesey, F. J. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.11.095 · Cited by 159 · see citing works
Boivin, M., Pfister, V., Gaucherot, A., Ruffenach, F., Negroni, L., Sellier, C., & Charlet‐Berguerand, N. (2020) · The EMBO Journal · doi:10.15252/embj.2018100574 · Cited by 137 · see citing works
Marrone, L., Poser, I., Casci, I., Japtok, J., Reinhardt, P., Janosch, A., Andree, C., Lee, H. O., Moebius, C., Koerner, E., et al. (2018) · Stem Cell Reports · doi:10.1016/j.stemcr.2017.12.018 · Cited by 104 · see citing works
Roscic, A., Baldo, B., Crochemore, C., Marcellin, D., & Paganetti, P. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07435.x · Cited by 92 · see citing works
Expression of WIPI2B counteracts age-related decline in autophagosome biogenesis in neurons
Stavoe, A. K., Gopal, P. P., Gubas, A., Tooze, S. A., & Holzbaur, E. L. (2019) · eLife · doi:10.7554/elife.44219 · Cited by 82 · see citing works
Sphingosine kinase 1-associated autophagy differs between neurons and astrocytes
Moruno-Manchon, J. F., Uzor, N.-E., Ambati, C. R., Shetty, V., Putluri, N., Jagannath, C., McCullough, L. D., & Tsvetkov, A. S. (2018) · Cell Death & Disease · doi:10.1038/s41419-018-0599-5 · Cited by 36 · see citing works
Self-citationThe activation of autophagy protects neurons and astrocytes against bilirubin-induced cytotoxicity
Qaisiya, M., Mardešić, P., Pastore, B., Tiribelli, C., & Bellarosa, C. (2017) · Neuroscience Letters · doi:10.1016/j.neulet.2017.09.056 · Cited by 35 · see citing works
- Authors
- Tsvetkov, A. S., Miller, J., Arrasate, M., Wong, J. S., Pleiss, M. A., & Finkbeiner, S.
- Affiliations
- University of California, San Francisco (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-09-10
- Volume
- 107
- Issue
- 39
- Pages
- 16982-16987
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2947884
- OpenAlex
- W2045647507
- Cited by
- 266
- References
- 33
- Citations by year
- 2026: 9 · 2025: 8 · 2024: 7 · 2023: 5 · 2022: 12 · 2021: 23 · 2020: 21 · 2019: 19 · 2018: 20 · 2017: 24 · 2016: 20 · 2015: 17 · 2014: 22 · 2013: 25 · 2012: 19
- FWCI
- 13.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Hereditary Disease Foundation
- Gladstone Institutes
- Tokyo Medical and Dental University
- National Institutes of Health (1c06rr018928-01, AG‐022074, NS045191)
- University of California, San Diego
- University of California, San Francisco
- National Institute on Aging (P01AG022074)
- National Institute of General Medical Sciences
- National Institute of Neurological Disorders and Stroke (R01NS039746, R01NS045191)
- National Center for Research Resources (C06-RR-018928)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- autophagy, Huntington's disease, neuronal autophagy, phenoxazine, neuroprotection, protein aggregation, neurodegenerative proteinopathies, structure-activity relationship, pharmacophore, mTOR-independent autophagy
- MeSH terms
- Animals, Autophagy, Cells, Cultured, Huntington Disease, Neurons, Oxazines, Drug Approval, Protein Serine-Threonine Kinases, Protein Folding, Neuroprotective Agents, Cytoprotection, Intracellular Signaling Peptides and Proteins, Proto-Oncogene Proteins c-akt, Mice, Rats, TOR Serine-Threonine Kinases
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