Lysosomal TPCN (two pore segment channel) inhibition ameliorates beta-amyloid pathology and mitigates memory impairment in Alzheimer disease
Open accessAbstract
Impairment of the macroautophagy/autophagy-lysosomal pathway (ALP) can lead to amyloid plaque accumulation in Alzheimer disease (AD); however, the underlying mechanism remains unresolved. This study revealed a mechanism of ALP impairment mediated by gain-of-function of lysosomal TPCN2/TPC2 (two pore segment channel 2) and suggests a molecular target for AD intervention. Using mutant PSEN1/PS1 (presenilin 1)-expressing human neuroblastoma SH-SY5Y and familial AD fibroblasts collected from human patients, we showed lysosomal pH was increased in AD cells due to exaggerated TPCN2-mediated calcium (Ca2+) release which increases lysosomal pH and compromises ALP degradation. Genetic knockdown or pharmacological inhibition of the TPCN2 channel restored lysosomal Ca2+ homeostasis, acidity of the lysosome and ALP function. Furthermore, AD mice (5xFAD) that had received treatment with the TPCN2 inhibitor tetrandrine for 6 months or injection of AAV-shTpcn2 to knock down Tpcn2 showed reduction in amyloid plaques in cortical and hippocampal regions. These treatments also improved spine morphology and density and corrected cognitive deficits in 5xFAD mice assayed by immunohistochemistry, behavioral tests, and electrophysiological measurements, respectively. Taken together, these findings reveal a previously under-appreciated role of lysosomal TPCN2 in ALP impairment of AD. They also suggest targeting the lysosomal TPCN2 can serve as a therapeutic strategy for AD treatment in future drug development.Abbreviations Aβ: β-amyloid; AD: Alzheimer disease; AIF1/IBA1: allograft inflammatory factor 1; ALP: autophagy-lysosomal pathway; APP: amyloid beta precursor protein; ATP6V1B1/V-ATPase V1b1: ATPase H+ transporting V1 subunit B1; AVs: autophagy vacuoles; BAF: bafilomycin A1; CFC: contextual/cued fear conditioning assay; CHX: Ca2+/H+ exchanger; CTF-β: carboxy-terminal fragment derived from β-secretase; CTSD: cathepsin D; fAD: familial Alzheimer disease; GFAP: glial fibrillary acidic protein; LAMP1: lysosomal associated membrane protein 1; LTP: long‐term potentiation; MCOLN1/TRPML1: mucolipin 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAPT: microtubule associated protein tau; MWM: Morris water maze; NFT: neurofibrillary tangles; PFC: prefrontal cortex; PSEN1: presenilin 1; SQSTM1/p62: sequestosome 1; TBS: theta burst stimulation; TEM: transmission electronic microscopy; TPCN2/TPC2: two pore segment channel 2; WT: wild-type; V-ATPase: vacuolar type H+-ATPase
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
PS1 mutations may lead to opening of the two pore segment channel 2, whose markedly enhanced activity greatly promotes lysosomal calcium efflux and lysosomal alkalinization.
“Another study suggested that PS1 mutations may lead to the opening of another calcium ion channel, two pore segment channel 2 (TPCN2), whose markedly enhanced activity greatly promotes lysosomal calcium efflux and lysosomal alkalinization.270”
From Recent advances in Alzheimer's disease: Mechanisms, clinical trials and new drug development strategies. (2024) · cites this paper as [270]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Levine, B., & Klionsky, D. J. (2004) · Developmental Cell · doi:10.1016/s1534-5807(04)00099-1 · Cited by 3,671 · see citing works
Klionsky, 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-citationAutophagy: from phenomenology to molecular understanding in less than a decade
Klionsky, D. J. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2245 · Cited by 1,938 · see citing works
Advanced methods of microscope control using μManager software
Edelstein, A., Tsuchida, M. A., Amodaj, N., Pinkard, H., Vale, R. D., & Stuurman, N. (2014) · Journal of Biological Methods · doi:10.14440/jbm.2014.36 · Cited by 1,927 · see citing works
Extensive Involvement of Autophagy in Alzheimer Disease: An Immuno-Electron Microscopy Study
Nixon, R. A., Wegiel, J., Kumar, A., Yu, W. H., Peterhoff, C., Cataldo, A., & Cuervo, A. M. (2005) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/64.2.113 · Cited by 1,588 · see citing works
Lee, J.-H., Yu, W. H., Kumar, A., Lee, S., Mohan, P. S., Peterhoff, C. M., Wolfe, D. M., Martinez-Vicente, M., Massey, A. C., Sovak, G., et al. (2010) · Cell · doi:10.1016/j.cell.2010.05.008 · Cited by 1,212 · see citing works
Pickford, F., Masliah, E., Britschgi, M., Lucin, K. M., Narasimhan, R., Jaeger, P. A., Small, S., Spencer, B., Rockenstein, E., Levine, B., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci33585 · Cited by 1,186 · 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
Macroautophagy—a novel β-amyloid peptide-generating pathway activated in Alzheimer's disease
Yu, W. H., Cuervo, A. M., Kumar, A., Peterhoff, C. M., Schmidt, S. D., Lee, J.-H., Mohan, P. S., Mercken, M., Farmery, M. R., Tjernberg, L. O., et al. (2005) · The Journal of Cell Biology · doi:10.1083/jcb.200505082 · Cited by 967 · see citing works
NAADP mobilizes calcium from acidic organelles through two-pore channels
Calcraft, P. J., Ruas, M., Pan, Z., Cheng, X., Arredouani, A., Hao, X., Tang, J., Rietdorf, K., Teboul, L., Chuang, K.-T., et al. (2009) · Nature · doi:10.1038/nature08030 · Cited by 760 · see citing works
Autophagy Failure in Alzheimer's Disease – Locating the Primary Defect
Nixon, R., & Yang, D.-S. (2011) · Neurobiology of Disease · doi:10.1016/j.nbd.2011.01.021 · Cited by 634 · see citing works
Two-pore channels control Ebola virus host cell entry and are drug targets for disease treatment
Sakurai, Y., Kolokoltsov, A. A., Chen, C., Tidwell, M. W., Bauta, W. E., Klugbauer, N., Grimm, C. M., Wahl‐Schott, C., Biel, M., & Davey, R. A. (2015) · Science · doi:10.1126/science.1258758 · Cited by 548 · see citing works
Wang, X., Zhang, X., Dong, X., Samie, M., Li, X., Cheng, X., Goschka, A., Shen, D., Zhou, Y., Harlow, J., et al. (2012) · Cell · doi:10.1016/j.cell.2012.08.036 · Cited by 530 · see citing works
Crosstalk between autophagy and inflammatory signalling pathways: balancing defence and homeostasis
Cadwell, K. (2016) · Nature reviews. Immunology · doi:10.1038/nri.2016.100 · Cited by 478 · see citing works
A Hundred Years of Alzheimer's Disease Research
Hardy, J. (2006) · Neuron · doi:10.1016/j.neuron.2006.09.016 · Cited by 467 · see citing works
Cheung, K., Shineman, D. W., Müller, M., Cárdenas, C., Mei, L., Yang, J., Tomita, T., Iwatsubo, T., Lee, V. M. ‐., & Foskett, J. K. (2008) · Neuron · doi:10.1016/j.neuron.2008.04.015 · Cited by 449 · see citing works
Self-citationAutophagy and Alzheimer’s Disease: From Molecular Mechanisms to Therapeutic Implications
Uddin, M. S., Stachowiak, A., Mamun, A. A., Tzvetkov, N. T., Takeda, S., Atanasov, A. G., Bergantin, L. B., Abdel‐Daim, M. M., & Stankiewicz, A. M. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00004 · Cited by 440 · see citing works
Essential requirement for two-pore channel 1 in NAADP-mediated calcium signaling
Brailoiu, E., Churamani, D., Cai, X., Schrlau, M. G., Brailoiu, G. C., Gao, X. Y., Hooper, R., Boulware, M. J., Dun, N. J., Marchant, J. S., et al. (2009) · The Journal of Cell Biology · doi:10.1083/jcb.200904073 · Cited by 401 · see citing works
Lee, J.-H., McBrayer, M. K., Wolfe, D. M., Haslett, L. J., Kumar, A., Sato, Y., Lie, P. P. Y., Mohan, P., Coffey, E. E., Kompella, U., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.07.050 · Cited by 358 · see citing works
Pasternak, S., Bagshaw, R. D., Guiral, M., Zhang, S., Ackerley, C. A., Pak, B. J., Callahan, J. W., & Mahuran, D. J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m304009200 · Cited by 314 · see citing works
SERCA pump activity is physiologically regulated by presenilin and regulates amyloid β production
Green, K. N., Demuro, A., Akbari, Y., Hitt, B. D., Smith, I. F., Parker, I., & LaFerla, F. M. (2008) · The Journal of Cell Biology · doi:10.1083/jcb.200706171 · Cited by 305 · see citing works
Virus-specific memory T cells populate tumors and can be repurposed for tumor immunotherapy
Rosato, P. C., Wijeyesinghe, S., Stolley, J. M., Nelson, C. E., Davis, R. L., Manlove, L. S., Pennell, C. A., Blazar, B. R., Chen, C. C., Geller, M. A., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-08534-1 · Cited by 304 · see citing works
Yu, W. H., Kumar, A., Peterhoff, C., Shapiro Kulnane, L., Uchiyama, Y., Lamb, B. T., Cuervo, A. M., & Nixon, R. A. (2004) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2004.05.010 · Cited by 279 · see citing works
The two-pore channel TPCN2 mediates NAADP-dependent Ca2+-release from lysosomal stores
Zong, X., Schieder, M., Cuny, H., Fenske, S., Grüner, C., Rötzer, K., Griesbeck, O., Harz, H., Biel, M., & Wahl‐Schott, C. (2009) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-009-0690-y · Cited by 275 · see citing works
Ruas, M., Rietdorf, K., Arredouani, A., Davis, L. C., Lloyd‐Evans, E., Koegel, H., Funnell, T. M., Morgan, A. J., Ward, J. A., Watanabe, K., et al. (2010) · Current Biology · doi:10.1016/j.cub.2010.02.049 · Cited by 247 · see citing works
Growth hormone regulates neuroendocrine responses to weight loss via AgRP neurons
Furigo, I. C., Teixeira, P. D. S., de Souza, G. O., Couto, G. C. L., Romero, G. G., Perelló, M., Frazão, R., Elias, L. L. K., Metzger, M., List, E. O., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-08607-1 · Cited by 230 · see citing works
Golgi-Cox Staining Step by Step
Zaqout, S., & Kaindl, A. M. (2016) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2016.00038 · Cited by 227 · see citing works
Chakroborty, S., Goussakov, I. V., Miller, M. B., & Stutzmann, G. E. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.2047-09.2009 · Cited by 209 · see citing works
Cheung, K., Mei, L., Mak, D. D., Hayashi, I., Iwatsubo, T., Kang, D. E., & Foskett, J. K. (2010) · Science Signaling · doi:10.1126/scisignal.2000818 · Cited by 208 · see citing works
Self-citationCoen, K., Flannagan, R. S., Baron, S., Carraro-Lacroix, L. R., Wang, D., Vermeire, W., Michiels, C., Munck, S., Baert, V., Sugita, S., et al. (2012) · Journal of Cell Biology · doi:10.1083/jcb.201201076 · Cited by 208 · see citing works
Dual roles for autophagy: Degradation and secretion of Alzheimer's disease Aβ peptide
Nilsson, P., & Saido, T. C. (2014) · BioEssays · doi:10.1002/bies.201400002 · Cited by 202 · see citing works
High susceptibility to fatty liver disease in two-pore channel 2-deficient mice
Grimm, C. M., Holdt, L. M., Chen, C., Hassan, S., Müller, C., Jörs, S., Cuny, H., Kissing, S., Schröder, B., Butz, E. S., et al. (2014) · Nature Communications · doi:10.1038/ncomms5699 · Cited by 199 · see citing works
Rosato, A. S., Montefusco, S., Soldati, C., Paola, S. D., Capuozzo, A., Monfregola, J., Polishchuk, E., Amabile, A., Grimm, C. M., Lombardo, A., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-13572-w · Cited by 199 · see citing works
Brailoiu, E., Rahman, T., Churamani, D., Prole, D. L., Brailoiu, G. C., Hooper, R., Taylor, C. W., & Patel, S. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.162073 · Cited by 169 · see citing works
Function and dysfunction of two-pore channels
Patel, S. (2015) · Science Signaling · doi:10.1126/scisignal.aab3314 · Cited by 169 · see citing works
Song, J., Malampati, S., Zeng, Y. X., Durairajan, S. S. K., Yang, C., Tong, B. C., Iyaswamy, A., Shang, W., Sreenivasmurthy, S. G., Zhu, Z., et al. (2019) · Aging Cell · doi:10.1111/acel.13069 · Cited by 161 · see citing works
Self-citationCupers, P., Bentahir, M., Craessaerts, K., Orlans, I., Vanderstichele, H., Säftig, P., Strooper, B. D., & Annaert, W. G. (2001) · The Journal of Cell Biology · doi:10.1083/jcb.200104045 · Cited by 158 · see citing works
Cataldo, A. M., Peterhoff, C. M., Schmidt, S. D., Terio, N. B., Duff, K., Beard, M. E., Mathews, P. M., & Nixon, R. A. (2004) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/63.8.821 · Cited by 157 · see citing works
Neely, K. M., Green, K. N., & LaFerla, F. M. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.5156-10.2010 · Cited by 141 · see citing works
Dysregulation of Nutrient Sensing and CLEARance in Presenilin Deficiency
Reddy, K., Cusack, C. L., Nnah, I. C., Khayati, K., Saqcena, C., Huynh, T., Noggle, S., Ballabio, A., & Dobrowolski, R. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.02.006 · Cited by 136 · see citing works
Lin-Moshier, Y., Keebler, M. V., Hooper, R., Boulware, M. J., Liu, X., Churamani, D., Abood, M. E., Walseth, T. F., Brailoiu, E., Patel, S., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1407004111 · Cited by 123 · see citing works
Zhang, X., Garbett, K., Veeraraghavalu, K., Wilburn, B., Gilmore, R., Mirnics, K., & Sisodia, S. S. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.0556-12.2012 · Cited by 122 · see citing works
Tuning the ion selectivity of two-pore channels
Guo, J., Zeng, W., & Jiang, Y. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1616191114 · Cited by 120 · see citing works
Enhanced Ryanodine‐Mediated Calcium Release in Mutant PS1‐Expressing Alzheimer's Mouse Models
Stutzmann, G. E., Smith, I. F., Caccamo, A., Oddo, S., Parker, I., & LaFerla, F. M. (2007) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1379.025 · Cited by 118 · see citing works
TRPML1: An Ion Channel in the Lysosome
Wang, W., Zhang, X., Gao, Q., & Xu, H. (2014) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-54215-2_24 · Cited by 114 · see citing works
He, F.-Q., Qiu, B., Zhang, X.-H., Li, T.-K., Xie, Q., Cui, D.-J., Huang, X.-L., & Gan, H. (2011) · Brain Research · doi:10.1016/j.brainres.2011.01.103 · Cited by 113 · see citing works
Wilson, C., Murphy, D. D., Giasson, B. I., Zhang, B., Trojanowski, J. Q., & Lee, V. M. ‐. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200403061 · Cited by 106 · see citing works
Galione, A., Evans, A. M., Ma, J., Parrington, J., Arredouani, A., Cheng, X., & Zhu, M. X. (2009) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-009-0682-y · Cited by 93 · see citing works
Tetrandrine blocks autophagic flux and induces apoptosis via energetic impairment in cancer cells
Qiu, W., Su, M., Xie, F., Ai, J., Ren, Y., Zhang, J., Guan, R., He, W., Gong, Y., & Guo, Y. (2014) · Cell Death and Disease · doi:10.1038/cddis.2014.84 · Cited by 88 · see citing works
Tong, B. C., Lee, C. S.-K., Cheng, W.-H., Lai, K., Foskett, J. K., & Cheung, K. (2016) · Science Signaling · doi:10.1126/scisignal.aaf1371 · Cited by 87 · see citing works
Self-citationComplement C7is a novel risk gene for Alzheimer's disease in Han Chinese
Zhang, D., Fan, Y., Xu, M., Wang, G., Wang, D., Li, J., Kong, L., Zhou, H., Luo, R., Bi, R., et al. (2018) · National Science Review · doi:10.1093/nsr/nwy127 · Cited by 86 · see citing works
Self-citationRuas, M., Chuang, K., Davis, L. C., Al-Douri, A., Tynan, P. W., Tunn, R., Teboul, L., Galione, A., & Parrington, J. (2014) · Molecular and Cellular Biology · doi:10.1128/mcb.00113-14 · Cited by 85 · see citing works
TPCs: Endolysosomal channels for Ca 2+ mobilization from acidic organelles triggered by NAADP
Zhu, M. X., Ma, J., Parrington, J., Galione, A., & Evans, A. M. (2010) · FEBS Letters · doi:10.1016/j.febslet.2010.02.028 · Cited by 77 · see citing works
Two-pore channels at the intersection of endolysosomal membrane traffic
Marchant, J. S., & Patel, S. (2015) · Biochemical Society Transactions · doi:10.1042/bst20140303 · Cited by 58 · see citing works
Tetrandrine is a potent cell autophagy agonist via activated intracellular reactive oxygen species
Wang, H., Liu, T., Li, L., Wang, Q., Yu, C., Liu, X., & Li, W. (2015) · Cell & Bioscience · doi:10.1186/2045-3701-5-4 · Cited by 52 · see citing works
Ambrosio, A. L., Boyle, J. A., & Pietro, S. M. D. (2015) · Molecular Biology of the Cell · doi:10.1091/mbc.e15-01-0058 · Cited by 49 · see citing works
The Potential of Tetrandrine as a Protective Agent for Ischemic Stroke
Chen, Y., Tsai, Y., & Tseng, S. (2011) · Molecules · doi:10.3390/molecules16098020 · Cited by 49 · see citing works
Imaging approaches to measuring lysosomal calcium
Morgan, A. J., Davis, L. C., & Galione, A. (2015) · Methods in cell biology · doi:10.1016/bs.mcb.2014.10.031 · Cited by 46 · see citing works
TPC2 mediates autophagy progression and extracellular vesicle secretion in cancer cells
Sun, W., & Yue, J. (2018) · Experimental Cell Research · doi:10.1016/j.yexcr.2018.07.013 · Cited by 45 · see citing works
Chapter 6 Monitoring Autophagy in Alzheimer's Disease and Related Neurodegenerative Diseases
Yang, D., Lee, J., & Nixon, R. A. (2009) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(08)04006-8 · Cited by 34 · see citing works
NAADP/TPC2/Ca2+Signaling Inhibits Autophagy
Lü, Y., Hao, B., Graeff, R. M., & Yue, J. (2013) · Communicative & Integrative Biology · doi:10.4161/cib.27595 · Cited by 28 · see citing works
Huang, Y., & Hong, C. (1998) · Cardiovascular Drug Reviews · doi:10.1111/j.1527-3466.1998.tb00341.x · Cited by 24 · see citing works
Flagged first, then by citations
1 of the 63 references couldn’t be matched to a known paper.
Research works printed but not linked: 3
- Huang YT, Hong CY. Tetrandrine. Cardiovasc Drug Rev. 1998;16 (1):1-15.
- Lu Y, Hao B, Graeff R, et al. NAADP/TPC2/Ca 2+ signaling inhi- bits autophagy. Commun Integr Biol. 2013;6(6):e27595.
- Paxinos G, Watson C, Petrides M, et al.The marmoset brain in stereotaxic coordinates. Elsevier Academic Press, London, UK; 2012.
Cited by
Sorted by citations
Zhang, J., Zhang, Y., Wang, J., Xia, Y., Zhang, J., & Chen, L. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01911-3 · Cited by 1,138 · see citing works
“270 Thus, the relationship among PS1 gene mutations or de fi ciencies, lysosomal acidi fi cation, and lysosomal calcium ion dysregulation warrants further investigation.”
BackgroundMechanisms of autophagy–lysosome dysfunction in neurodegenerative diseases
Nixon, R. A., & Rubinsztein, D. C. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00757-5 · Cited by 435 · see citing works
“As discussed below, PSEN1 loss of function also releases calcium from lysosomes 19,108,117,127 via transient receptor potential channel mucolipin 1 (TRPML1; also known as mucolipin 1) 19,108 or two-pore channel protein 2 (TPC2) channels 129 .”
Cell death in pancreatic cancer: from pathogenesis to therapy
Chen, X., Zeh, H. J., Kang, R., Kroemer, G., & Tang, D. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00486-6 · Cited by 339 · see citing works
Lysosomes in senescence and aging
Tan, J. X., & Finkel, T. (2023) · EMBO Reports · doi:10.15252/embr.202357265 · Cited by 160 · see citing works
Self-citationNeuronal endolysosomal transport and lysosomal functionality in maintaining axonostasis
Roney, J. C., Cheng, X., & Sheng, Z. (2022) · The Journal of Cell Biology · doi:10.1083/jcb.202111077 · Cited by 87 · see citing works
Targeting autophagy in Alzheimer’s disease: Animal models and mechanisms
Zhang, X.-W., 澳门大学中华医药研究院中药质量研究国家重点实验室, 澳. 凼. 9., State Key Laboratory of Quality Research in Chinese Medicine, I. O. C. M. S., Zhu, X.-X., Tang, D.-S., Lu, J.-H., 佛山大学广东省动物分子设计与精准育种重点实验室, 广., & Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, G. E. T. C. O. G. P. (2023) · Zoological Research · doi:10.24272/j.issn.2095-8137.2023.294 · Cited by 77 · see citing works
Self-citationThe Emerging Roles of Autophagy in Human Diseases
Lei, Y., & Klionsky, D. J. (2021) · Biomedicines · doi:10.3390/biomedicines9111651 · Cited by 66 · see citing works
Tong, B. C., Huang, S., Wu, A. J., Iyaswamy, A., Ho, O. K.-Y., Kong, A. H.-Y., Sreenivasmurthy, S. G., Zhu, Z., Su, C.-F., Liu, J., et al. (2022) · Journal of Biomedical Science · doi:10.1186/s12929-022-00871-6 · Cited by 49 · see citing works
“The reduction of lysosomal calcium ions (Ca2+) drives the expulsion of hydrogen ions (H+) through the Ca2+/ H+ exchanger (CAX), thus leading to lysosomal alkalinization and impairment of the ALP [14].”
InfluentialSelf-citationCheng, D., Lei, Z., Chu, K., Lam, O. J. H., Chiang, C. Y., & Zhang, Z.-J. (2024) · Alzheimer s Research & Therapy · doi:10.1186/s13195-024-01462-3 · Cited by 46 · see citing works
Jung, Y. H., Chae, C. W., & Han, H. J. (2024) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01282-3 · Cited by 42 · see citing works
Rahman, M. A., Saikat, A. S. M., Rahman, M. S., Islam, M., Parvez, M. A. K., & Kim, B. (2023) · Cells · doi:10.3390/cells12030458 · Cited by 41 · see citing works
“lysosome fusion by disrupting the Ca2+ gradients required for this pathway [87].”
BackgroundGuan, X.-J., Deng, Z.-Q., Liu, J., Su, C.-F., Tong, B. C., Zhu, Z., Sreenivasmurthy, S. G., Kan, Y., Lu, K.-J., Chu, C. P., et al. (2024) · Acta Pharmacologica Sinica · doi:10.1038/s41401-023-01197-1 · Cited by 41 · see citing works
Self-citationKlotho an Autophagy Stimulator as a Potential Therapeutic Target for Alzheimer’s Disease: A Review
Fung, T., Iyaswamy, A., Sreenivasmurthy, S. G., Krishnamoorthi, S., Guan, X.-J., Zhu, Z., Su, C.-F., Liu, J., Kan, Y., Zhang, Y., et al. (2022) · Biomedicines · doi:10.3390/biomedicines10030705 · Cited by 41 · see citing works
“Thus, autophagy may take part in AD, and the autophagy mechanism may be a viable therapeutic target for treating AD [54,59].”
BackgroundSelf-citationJin, S., Wang, X., Xiang, X., Wu, Y., Hu, J., Li, Y., Dong, Y. L., Tan, Y., & Wu, X. G. (2021) · International Immunopharmacology · doi:10.1016/j.intimp.2021.108335 · Cited by 32 · see citing works
TRPMLs and TPCs: targets for lysosomal storage and neurodegenerative disease therapy?
Krogsaeter, E., Rosato, A. S., & Grimm, C. (2022) · Cell Calcium · doi:10.1016/j.ceca.2022.102553 · Cited by 31 · see citing works
Neurodegenerative Lysosomal Storage Disorders: TPC2 Comes to the Rescue!
Castro, S. P., Kudrina, V., Jaślan, D., Böck, J., Rosato, A. S., & Grimm, C. M. (2022) · Cells · doi:10.3390/cells11182807 · Cited by 29 · see citing works
“[45,46] showed data to exclude the role of TPC2 instead.”
BackgroundResultInfluentialCalcium signaling hypothesis: A non-negligible pathogenesis in Alzheimer’s disease
Wang, M., Zhang, H., Liang, J., Huang, J., Wu, T., & Chen, N. (2025) · Journal of Advanced Research · doi:10.1016/j.jare.2025.01.007 · Cited by 25 · see citing works
Geng, M., Zhao, F., Lu, H., Li, F., Wang, J., Liu, C., & Min, W. (2022) · Food Research International · doi:10.1016/j.foodres.2022.111311 · Cited by 24 · see citing works
Iyaswamy, A., Lu, K., Guan, X.-J., Kan, Y., Su, C.-F., Liu, J., Jaganathan, R., Vasudevan, K., Paul, J., Thakur, A., et al. (2023) · Biomedicines · doi:10.3390/biomedicines11072056 · Cited by 24 · see citing works
Self-citationHadi, F., Mortaja, M., & Hadi, Z. (2024) · Cell Biochemistry and Function · doi:10.1002/cbf.4085 · Cited by 23 · see citing works
Chin, M. Y., Ang, K.-H., Davies, J. L., Alquézar, C., Garda, V. G., Rooney, B., Leng, K., Kampmann, M., Arkin, M. R., & Kao, A. W. (2022) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.1c00804 · Cited by 18 · see citing works
Fu, J., Song, W., Song, X., Li, F., Wang, X., Leng, Y., Wang, J., Liu, C., & Min, W. (2023) · Foods · doi:10.3390/foods12122329 · Cited by 18 · see citing works
“Timely intervention in cognitive impairment plays a critical role in delaying the progression of the disease [3].”
BackgroundLaparra, I. C., Juárez‐Escoto, E., Vicario‐Abejón, C., Moratalla, R., & García‐Sanz, P. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1087072 · Cited by 17 · see citing works
“This is due to the cellular plasticity of skin fibroblasts, which endows them with the potential to be easily cultured and have levels of gene expression and damage accumulation similar to those of neurons (Bell et al., 2018; Tong et al., 2022).”
ResultKrishnamoorthi, S., Iyaswamy, A., Sreenivasmurthy, S. G., Thakur, A., Vasudevan, K., Kumar, G., Guan, X.-J., Lu, K., Gaurav, I., Su, C.-F., et al. (2023) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-023-10083-w · Cited by 17 · see citing works
“The impairment of the autophagy-lysosomal pathway (ALP), one of the major degradative processes involved in the clearance of aggregated proteins, has been closed linked with the AD progression (Boland et al. 2018; Tong et al. 2021; Zheng et al. 2021).”
BackgroundMethodInfluentialSelf-citationGiuliano, S., Montemagno, C., Domdom, M. A., Teisseire, M., Brest, P., Klionsky, D. J., Hofman, P. M., Pagès, G., & Mograbi, B. (2023) · Autophagy · doi:10.1080/15548627.2023.2214960 · Cited by 17 · see citing works
Two-pore channels: going with the flows
Morgan, A. J., Martucci, L. L., Davis, L. C., & Galione, A. (2022) · Biochemical Society Transactions · doi:10.1042/bst20220229 · Cited by 16 · see citing works
Tedeschi, V., Sapienza, S., Ciancio, R., Canzoniero, L. M. T., Pannaccione, A., & Secondo, A. (2024) · Current Neuropharmacology · doi:10.2174/1570159x22666240517101846 · Cited by 16 · see citing works
“Therefore, genetic knockdown or pharmacological inhibition of this channel restores lysosomal Ca 2+ homeostasis and promotes reduction in cortical and hippocampal amyloid plaques in AD mice [71].”
Targeting the two-pore channel 2 in cancer progression and metastasis
Skelding, K. A., Barry, D. L., Theron, D. Z., & Lincz, L. F. (2022) · Exploration of Targeted Anti-tumor Therapy · doi:10.37349/etat.2022.00072 · Cited by 15 · see citing works
“Importantly, pharmacological inhibitors of TPC2 are potentially beneficial for the treatment of Ebola virus, SARS-CoV-2, Parkinson’s disease, and Alzheimer’s disease [35, 40, 41, 43], highlighting that TPC2 may be a suitable drug target for a plethora of pathophysiological processes.”
BackgroundPlasma exosomes impair microglial degradation of α‐synuclein through V‐ATPase subunit V1G1
Li, Y., Wang, Y., Kou, L., Yin, S., Chi, X., Sun, Y., Wu, J., Jin, Z., Zhou, Q., Zou, W., et al. (2024) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14738 · Cited by 13 · see citing works
“…the V- ATPases-dependent lysosomal pH and maintenance of lysosomal physiological functions are tightly associated with neurodegeneration diseases, 7 such as Alzheimer's dis - ease (AD), PD, and lysosomal storage diseases, 8,9 where lysosomes can degrade and clear pathological protein aggregates.”
BackgroundGregori, M., Pereira, G. J. S., Allen, R., West, N., Chau, K., Cai, X., Bostock, M. P., Bolsover, S. R., Keller, M., Lee, C., et al. (2025) · The Journal of Cell Biology · doi:10.1083/jcb.202412055 · Cited by 13 · see citing works
Current aspects of targeting cellular senescence for the therapy of neurodegenerative diseases
Jaganathan, R., Iyaswamy, A., Krishnamoorthi, S., Thakur, A., Durairajan, S. S. K., Yang, C., & Wankhar, D. (2025) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2025.1627921 · Cited by 11 · see citing works
Self-citationPathological Functions of Lysosomal Ion Channels in the Central Nervous System
Cen, J.-K., Hu, N., Shen, J., Gao, Y., & Lu, H.-J. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25126565 · Cited by 10 · see citing works
“While TPC2 antagonists could restore lysosomal Ca 2+ and pH and rescue autophagy [197], prolonged inhibition of TPC2 may result in trafficking defects and cholesterol overload, posing potential risks for neurodegenerative disease development [103].”
BackgroundHou, M., Zhang, Z., Fan, Z.-X., Huang, L., & Wang, L. (2024) · Medicine · doi:10.1097/md.0000000000039405 · Cited by 9 · see citing works
Wu, H., Zhang, Q., Xu, P., Chen, J., Duan, L., Xu, F., & Zhang, F. (2023) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.2c08718 · Cited by 9 · see citing works
Alharbi, A., & Parrington, J. (2025) · Pharmacological Research · doi:10.1016/j.phrs.2025.107655 · Cited by 6 · see citing works
Wang, F., Liu, Y., Wen, J., Tan, A., Deng, Y., Wang, L., Gong, H., Lai, Y., Huang, Z., & Zhao, F. (2025) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2025.110258 · Cited by 6 · see citing works
Diabetes mellitus and Alzheimer's disease: Vacuolar adenosine triphosphatase as a potential link
Guo, B., Li, Q., Liu, X. M., Luo, G., Wu, Y., & Nie, J. (2024) · European Journal of Neuroscience · doi:10.1111/ejn.16286 · Cited by 5 · see citing works
Cai, J., Liao, F., Mao, Y., Liu, S., Wu, X., Wang, S., Wang, S., Shan, G., & Wu, S. (2024) · Experimental Eye Research · doi:10.1016/j.exer.2024.110129 · Cited by 5 · see citing works
Missense and loss‐of‐function variants at GWAS loci in familial Alzheimer's disease
Gunasekaran, T. I., Reyes‐Dumeyer, D., Faber, K. M., Goate, A., Boeve, B. F., Cruchaga, C., Pericak‐Vance, M. A., Haines, J. L., Rosenberg, R. N., Tsuang, D. W., et al. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.14221 · Cited by 4 · see citing works
Zhang, Y., Yang, X., Gong, M., Yang, Y., Chen, R., Li, Y., Wang, A., Xu, Y., & Zeng, Q. (2025) · Human & Experimental Toxicology · doi:10.1177/09603271251356256 · Cited by 3 · see citing works
“53 Impaired autophagy prevents timely clearance of amyloid or aggregation-prone proteins, accelerating Alzheimer ’ s disease (AD) progression.”
Zhang, J., Zhang, X., Wu, J., Mu, G., & Wu, X. (2026) · Foods · doi:10.3390/foods15061080 · Cited by 3 · see citing works
“…gene expression analysis, total RNA was extracted using a dedicated kit, reverse-transcribed into cDNA, and subjected to a StepOne Real-Time PCR System (Applied Biosystems, Foster City, CA, USA) using a Viia 7 system with gene-specific primers (Table 1) [20]. https://doi.org/10.3390/foods15061080”
InfluentialFeng, H., Mou, Q., Yan, X., Zhang, Z., LIANG, T., Peng, F., Zhang, T., Yan, M., Liang, J., Liu, W., et al. (2026) · Toxicology Research · doi:10.1093/toxres/tfag008 · Cited by 2 · see citing works
Xing, L., Liu, A., Gao, W., Li, J., Yao, M., Song, J., Duan, P., & Li, H. (2026) · Ageing Research Reviews · doi:10.1016/j.arr.2026.103145 · Cited by 2 · see citing works
Self-citationGe, C., Wang, K., Tang, H., Ke, Y., Wang, H., Fu, Q., Xiu, Y., Guo, Y., Jia, Y., Long, Z., et al. (2026) · Translational Neurodegeneration · doi:10.1186/s40035-026-00549-1 · Cited by 1 · see citing works
Deng, Z., Kan, Y., Liu, J., Ying, K. Y., Yang, Y., Guan, X., Xu, X., Su, C.-F., Lu, J., Lu, K., et al. (2026) · Cell Death and Differentiation · doi:10.1038/s41418-026-01813-7 · Cited by 1 · see citing works
Self-citationCheng, D., Lei, Z.-G., Chu, K., Lam, O. J. H., Chiang, C. Y., & Zhang, Z.-J. (2024) · Figshare · doi:10.6084/m9.figshare.25734511
Tong, B. C., Huang, A. S., Wu, A. J., Iyaswamy, A., Ho, O. K.-Y., Kong, A. H.-Y., Sreenivasmurthy, S. G., Zhu, Z., Su, C., Liu, J., et al. (2022) · Figshare · doi:10.6084/m9.figshare.21384499
Self-citationATG5-FOXA3 Axis Contributes to Lysosomal Biogenesis and Auditory Function in Kölliker’s Organ
Chen, P., Zhang, J., Wang, Y., & Chen, J. (2026) · Biomedicines · doi:10.3390/biomedicines14040802
“Mutations in ATP6V1B1 and ATP6V0A4, lysosomal proton pump genes, result in syndromic deafness with distal renal tubular acidosis [35,36].”
Dubrovina, N. I., Ovsyukova, M. V., Gao, V., & Tikhonova, M. A. (2026) · Neuroscience and Behavioral Physiology · doi:10.1007/s11055-026-02047-3
“The development of microgliosis and astrocytosis, in parallel with impairment to the ALP (autophagic-lysosomal pathway) and decreased tau clearance by microglia, resulted in impaired CPAR and CRF in P301S mice (a model of tau pathology) [Tang et al., 2020; Tong et al., 2022a].”
- Authors
- Tong, B. C.-K., Wu, A. J., Huang, A. S., Dong, R., Malampati, S., Iyaswamy, A., Krishnamoorthi, S., Sreenivasmurthy, S. G., Zhu, Z., Su, C., Liu, J., Song, J., Lu, J.-H., Tan, J., Pan, W., Li, M., & Cheung, K.-H.
- Affiliations
- Hong Kong Baptist University (HK)
- School of Chinese Medicine and Mr. And Mrs. Ko Chi Ming Centre for Parkinson’s Disease Research, Hong Kong Baptist University, Hong Kong, China
- University of Hong Kong (HK)
- Medical College of Acupuncture-Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China
- Central South University (CN)
- Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences (CN)
- Corresponding author
- Cheung, King-Ho
- ORCID
- Venue
- Autophagy
- Publisher
- Informa UK Limited
- Published
- 2021-07-27
- Volume
- 18
- Issue
- 3
- Pages
- 624-642
- ISSN
- 1554-8627 (ISSN-L)
- 1554-8635
- PMC
- PMC9037479
- OpenAlex
- W3186600809
- Cited by
- 49
- References
- 63
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 14 · 2023: 9 · 2022: 10 · 2021: 3
- FWCI
- 5.65
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Autophagy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Hong Kong Baptist University (HKBU RC-EMF02/17)
- Guangdong Natural Science Foundation (2019A1515011756)
- Health and Medical Research Fund (15163421, 15163481, 17182541, 17182551, 17182561)
- Research Grants Council, University Grants Committee (HKBU/17104514, HKBU/12101417, HKBU/12100618)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- lysosomal pH, autophagy-lysosome pathway, Alzheimer's disease, amyloid plaques, memory impairment, tetrandrine, presenilin 1, presenilin 2, 5xFAD mice, cognitive impairment
- MeSH terms
- Adenosine Triphosphatases, Alzheimer Disease, Autophagy, Humans, Lysosomes, Memory Disorders, Amyloid beta-Peptides, Vacuolar Proton-Translocating ATPases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
