Astragaloside IV reduces mutant Ataxin-3 levels and supports mitochondrial function in Spinocerebellar Ataxia Type 3.
Ataxin-3
/ genetics
Humans
Machado-Joseph Disease
/ drug therapy
Saponins
/ pharmacology
Triterpenes
/ pharmacology
Mitochondria
/ metabolism
Oxidative Stress
/ drug effects
Autophagy
/ drug effects
Cell Line, Tumor
Membrane Potential, Mitochondrial
/ drug effects
Antioxidants
/ pharmacology
Mutation
Mitochondrial Dynamics
/ drug effects
Repressor Proteins
Astragaloside IV
Autophagy
Mitochondrial dysfunction
Oxidative stress
Spinocerebellar ataxia type 3
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
29 10 2024
29 10 2024
Historique:
received:
20
03
2024
accepted:
24
10
2024
medline:
30
10
2024
pubmed:
30
10
2024
entrez:
30
10
2024
Statut:
epublish
Résumé
This study investigated the therapeutic effects of astragaloside IV (AST) on spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), a neurodegenerative disorder. Human neuroblastoma SK-N-SH cells expressing mutant ataxin-3 protein with 78 CAG repeats (MJD78) were employed as an in vitro model. Protein expression analysis demonstrated that AST treatment reduced mutant ataxin-3 protein expression and aggregation by enhancing the autophagic process in MJD78 cells. Elevated oxidative stress levels in MJD78 cells were significantly reduced following AST treatment, which also enhanced antioxidant capacity, as evidenced by flow cytometry and antioxidant enzyme activity assays. Furthermore, AST treatment ameliorated mitochondrial dysfunction in MJD78 cells, including improvements in mitochondrial membrane potential, respiration, and mitochondrial dynamics. In conclusion, AST administration increased antioxidant capacity, reduced both cellular and mitochondrial oxidative stress, and improved mitochondrial quality control processes through fusion, fission, and autophagy. These mechanisms collectively reduced intracellular mutant ataxin-3 protein aggregation, thereby achieving therapeutic efficacy in the SCA3 model.
Identifiants
pubmed: 39472629
doi: 10.1038/s41598-024-77763-2
pii: 10.1038/s41598-024-77763-2
doi:
Substances chimiques
Ataxin-3
EC 3.4.19.12
Saponins
0
Triterpenes
0
astragaloside A
3A592W8XKE
ATXN3 protein, human
EC 3.4.19.12
Antioxidants
0
Repressor Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
25979Subventions
Organisme : Ministry of Science and Technology in Taiwan
ID : MOST 109- 2314-B-371 -008 -MY3
Organisme : Changhua Christian Hospital
ID : 110- CCH-MST-168
Organisme : National Science and Technology Council
ID : NSTC 112-2314-B-371 -007 -MY3
Informations de copyright
© 2024. The Author(s).
Références
Li, X., Liu, H., Fischhaber, P. L. & Tang, T. S. <ArticleTitle Language=“En”>Toward therapeutic targets for SCA3: insight into the role of Machado–Joseph disease protein ataxin-3 in misfolded proteins clearance. Prog. Neurobiol. 132, 34–58 (2015).
pubmed: 26123252
doi: 10.1016/j.pneurobio.2015.06.004
Ikeda, H. et al. Expanded polyglutamine in the Machado–Joseph disease protein induces cell death in vitro and in vivo. Nat. Genet. 13, 196–202 (1996).
pubmed: 8640226
doi: 10.1038/ng0696-196
Lee, J. H. et al. n-Butylidenephthalide modulates autophagy to ameliorate neuropathological progress of spinocerebellar ataxia type 3 through mTOR pathway. Int. J. Mol. Sci. 22, 6339 (2021).
pubmed: 34199295
pmcid: 8231882
doi: 10.3390/ijms22126339
Paulino, R. & Nóbrega, C. Autophagy in Spinocerebellar Ataxia Type 3: From Pathogenesis to Therapeutics. Int. J. Mol. Sci. 24, 7405 (2023).
pubmed: 37108570
pmcid: 10138583
doi: 10.3390/ijms24087405
de Assis, A. M. et al. Peripheral oxidative stress biomarkers in spinocerebellar ataxia type 3/Machado–Joseph disease. Front. Neurol. 8, 485 (2017).
pubmed: 28979235
pmcid: 5611390
doi: 10.3389/fneur.2017.00485
Wu, Y. L. et al. Treatment with caffeic acid and resveratrol alleviates oxidative stress induced neurotoxicity in cell and drosophila models of spinocerebellar ataxia type3. Sci. Rep. 7, 11641 (2017).
pubmed: 28912527
pmcid: 5599504
doi: 10.1038/s41598-017-11839-0
Harmuth, T. et al. Mitochondrial dysfunction in spinocerebellar ataxia type 3 is linked to VDAC1 deubiquitination. Int. J. Mol. Sci. 23, 5933 (2022).
pubmed: 35682609
pmcid: 9180688
doi: 10.3390/ijms23115933
Nan, Y. et al. Protective role of vitamin B6 against mitochondria damage in Drosophila models of SCA3. Neurochem. Int. 144, 104979 (2021).
pubmed: 33535071
doi: 10.1016/j.neuint.2021.104979
Vasconcelos-Ferreira, A. et al. The autophagy‐enhancing drug carbamazepine improves neuropathology and motor impairment in mouse models of Machado–Joseph disease. Neuropathol. Appl. Neurobiol. 48, e12763 (2022).
pubmed: 34432315
doi: 10.1111/nan.12763
Sittler, A. et al. Deregulation of autophagy in postmortem brains of Machado-Joseph disease patients. Neuropathology. 38, 113–124 (2018).
pubmed: 29218765
doi: 10.1111/neup.12433
McLoughlin, H. S., Moore, L. R. & Paulson, H. L. Pathogenesis of SCA3 and implications for other polyglutamine diseases. Neurobiol. Dis. 134, 104635 (2020).
pubmed: 31669734
doi: 10.1016/j.nbd.2019.104635
Gandhi, S. & Abramov, A. Y. Mechanism of oxidative stress in neurodegeneration. Oxidative Med. Cell. Longev. 2012, 428010 (2012).
Singh, A., Kukreti, R., Saso, L. & Kukreti, S. Oxidative stress: a key modulator in neurodegenerative diseases. Molecules. 24, 1583 (2019).
pubmed: 31013638
pmcid: 6514564
doi: 10.3390/molecules24081583
Pardillo-Díaz, R., Pérez-García, P., Castro, C., Nunez-Abades, P. & Carrascal, L. Oxidative stress as a potential mechanism underlying membrane hyperexcitability in neurodegenerative diseases. Antioxidants. 11, 1511 (2022).
pubmed: 36009230
pmcid: 9405356
doi: 10.3390/antiox11081511
Aguilar, T. A. F., Navarro, B. C. H. & Pérez, J. A. M. Endogenous antioxidants: a review of their role in oxidative stress. A master regulator of oxidative stress-the transcription factor nrf2, 3–20 (2016).
Chen, C. M. et al. Shaoyao Gancao Tang (SG-Tang), a formulated Chinese medicine, reduces aggregation and exerts neuroprotection in spinocerebellar ataxia type 17 (SCA17) cell and mouse models. Aging (Albany NY). 11, 986 (2019).
pubmed: 30760647
doi: 10.18632/aging.101804
Mattson, M. P., Gleichmann, M. & Cheng, A. Mitochondria in neuroplasticity and neurological disorders. Neuron. 60, 748–766 (2008).
pubmed: 19081372
pmcid: 2692277
doi: 10.1016/j.neuron.2008.10.010
Ulasov, A. V., Rosenkranz, A. A., Georgiev, G. P. & Sobolev, A. S. Nrf2/Keap1/ARE signaling: Towards specific regulation. Life Sci. 291, 120111 (2022).
pubmed: 34732330
doi: 10.1016/j.lfs.2021.120111
Wang, D. K. et al. Mitochondrial dysfunction in oxidative stress-mediated intervertebral disc degeneration. Orthop. Surg. 14, 1569–1582 (2022).
pubmed: 35673928
pmcid: 9363752
doi: 10.1111/os.13302
Grimm, A. & Eckert, A. Brain aging and neurodegeneration: from a mitochondrial point of view. J. Neurochem. 143, 418–431 (2017).
pubmed: 28397282
pmcid: 5724505
doi: 10.1111/jnc.14037
Monzio Compagnoni, G. et al. The role of mitochondria in neurodegenerative diseases: the lesson from Alzheimer’s disease and Parkinson’s disease. Mol. Neurobiol. 57, 2959–2980 (2020).
pubmed: 32445085
doi: 10.1007/s12035-020-01926-1
Belenguer, P., Duarte, J. M., Schuck, P. F. & Ferreira, G. C. Mitochondria and the brain: bioenergetics and beyond. Neurotox. Res. 36, 219–238 (2019).
pubmed: 31152314
doi: 10.1007/s12640-019-00061-7
Pickles, S., Vigié, P. & Youle, R. J. Mitophagy and quality control mechanisms in mitochondrial maintenance. Curr. Biol. 28, R170–R185 (2018).
pubmed: 29462587
pmcid: 7255410
doi: 10.1016/j.cub.2018.01.004
Tang, W., Eisenbrand, G., Tang, W. & Eisenbrand, G. Astragalus membranaceus (Fisch.) Bge. Chinese Drugs of Plant Origin: Chemistry, Pharmacology, and Use in Traditional and Modern Medicine, 191–197 (1992).
Zhang, Z. et al. Astragaloside IV prevents MPP+-induced SH-SY5Y cell death via the inhibition of Bax-mediated pathways and ROS production. Mol. Cell. Biochem. 364, 209–216 (2012).
pubmed: 22278385
doi: 10.1007/s11010-011-1219-1
Zhang, X. & Chen, J. The mechanism of astragaloside IV promoting sciatic nerve regeneration. Neural Regeneration Res. 8, 2256 (2013).
Chen, F. et al. Astragaloside IV ameliorates cognitive impairment and neuroinflammation in an oligomeric aβ induced Alzheimer’s disease mouse model via inhibition of microglial activation and NADPH oxidase expression. Biol. Pharm. Bull. 44, 1688–1696 (2021).
pubmed: 34433707
doi: 10.1248/bpb.b21-00381
Costa, I. M. et al. Astragaloside IV supplementation promotes a neuroprotective effect in experimental models of neurological disorders: a systematic review. Curr. Neuropharmacol. 17, 648–665 (2019).
pubmed: 30207235
pmcid: 6712289
doi: 10.2174/1570159X16666180911123341
Liu, J., Meng, Q., Jing, H. & Zhou, S. Astragaloside IV protects against apoptosis in human degenerative chondrocytes through autophagy activation. Mol. Med. Rep. 16, 3269–3275 (2017).
pubmed: 28714008
pmcid: 5548053
doi: 10.3892/mmr.2017.6980
Tan, Y. Q., Chen, H. W. & Li, J. Astragaloside IV: an effective drug for the treatment of cardiovascular diseases. Drug. Des. Devel. Ther. 14, 3731–3746 (2020).
Gu, D. et al. EGFR mediates astragaloside IV-induced Nrf2 activation to protect cortical neurons against in vitro ischemia/reperfusion damages. Biochem. Biophys. Res. Commun. 457, 391–397 (2015).
pubmed: 25582778
doi: 10.1016/j.bbrc.2015.01.002
Watanabe, Y. et al. p62/SQSTM1-dependent autophagy of Lewy body-like α-synuclein inclusions. PloS one. 7, e52868 (2012).
pubmed: 23300799
pmcid: 3534125
doi: 10.1371/journal.pone.0052868
Liu, B. et al. EVA1A regulates hematopoietic stem cell regeneration via ER-mitochondria mediated apoptosis. Cell Death Dis. 14, 71 (2023).
pubmed: 36717548
pmcid: 9887066
doi: 10.1038/s41419-023-05559-9
Wu, Y. L. et al. In Vitro Efficacy and Molecular Mechanism of Curcumin Analog in Pathological Regulation of Spinocerebellar Ataxia Type 3. Antioxidants. 11, 1389 (2022).
pubmed: 35883884
pmcid: 9311745
doi: 10.3390/antiox11071389
Orr, H. T. Polyglutamine neurodegeneration: expanded glutamines enhance native functions. Curr. Opin. Genet. Dev. 22, 251–255 (2012).
pubmed: 22284692
pmcid: 3340441
doi: 10.1016/j.gde.2012.01.001
Ma, S., Attarwala, I. Y. & Xie, X. Q. SQSTM1/p62: a potential target for neurodegenerative disease. ACS Chem. Neurosci. 10, 2094–2114 (2019).
pubmed: 30657305
doi: 10.1021/acschemneuro.8b00516
Bortnik, S. & Gorski, S. M. Clinical applications of autophagy proteins in cancer: from potential targets to biomarkers. Int. J. Mol. Sci. 18, 1496 (2017).
pubmed: 28696368
pmcid: 5535986
doi: 10.3390/ijms18071496
Checa, J. & Aran, J. M. Reactive oxygen species: drivers of physiological and pathological processes. J. Inflamm. Res. 13, 1057–1073 (2020).
Gui, D. et al. Astragaloside IV, a novel antioxidant, prevents glucose-induced podocyte apoptosis in vitro and in vivo. PloS one. 7, e39824 (2012).
pubmed: 22745830
pmcid: 3382154
doi: 10.1371/journal.pone.0039824
Sun, Q. et al. Protective effects of astragaloside IV against amyloid beta1-42 neurotoxicity by inhibiting the mitochondrial permeability transition pore opening. PloS one. 9, e98866 (2014).
pubmed: 24905226
pmcid: 4048237
doi: 10.1371/journal.pone.0098866
Sienes Bailo, P. et al. The role of oxidative stress in neurodegenerative diseases and potential antioxidant therapies. Adv. Lab. Medicine/Avances en Med. de Laboratorio. 3, 342–350 (2022).
doi: 10.1515/almed-2022-0111
Liu, Z., Zhou, T., Ziegler, A. C., Dimitrion, P. & Zuo, L. Oxidative stress in neurodegenerative diseases: from molecular mechanisms to clinical applications. Oxidative Med. Cell. Longev. 2017, 252596 (2017).
Federico, A. et al. Mitochondria, oxidative stress and neurodegeneration. J. Neurol. Sci. 322, 254–262 (2012).
pubmed: 22669122
doi: 10.1016/j.jns.2012.05.030
Angelova, P. R. & Abramov, A. Y. Role of mitochondrial ROS in the brain: from physiology to neurodegeneration. FEBS Lett. 592, 692–702 (2018).
pubmed: 29292494
doi: 10.1002/1873-3468.12964
Chang, J. C. et al. Far-infrared radiation protects viability in a cell model of Spinocerebellar Ataxia by preventing polyQ protein accumulation and improving mitochondrial function. Sci. Rep. 6, 30436 (2016).
pubmed: 27469193
pmcid: 4965738
doi: 10.1038/srep30436
Hsu, J. Y. et al. The truncated C-terminal fragment of mutant ATXN3 disrupts mitochondria dynamics in spinocerebellar ataxia type 3 models. Front. Mol. Neurosci. 10, 196 (2017).
pubmed: 28676741
pmcid: 5476786
doi: 10.3389/fnmol.2017.00196
Youle, R. J. & Van Der Bliek, A. M. Mitochondrial fission, fusion, and stress. Science. 337, 1062–1065 (2012).
pubmed: 22936770
pmcid: 4762028
doi: 10.1126/science.1219855