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Open Access 01-03-2018 | Original Paper

Correction of Huntington’s Disease Phenotype by Genistein-Induced Autophagy in the Cellular Model

Authors: Karolina Pierzynowska, Lidia Gaffke, Aleksandra Hać, Jagoda Mantej, Natalia Niedziałek, Joanna Brokowska, Grzegorz Węgrzyn

Published in: NeuroMolecular Medicine | Issue 1/2018

Abstract

Huntington’s disease (HD) is a monogenic disorder, caused by mutations in the HTT gene which result in expansion of CAG triplets. The product of the mutated gene is misfolded huntingtin protein that forms aggregates leading to impairment of neuronal function, neurodegeneration, motor abnormalities and cognitive deficits. No effective cure is currently available for HD. Here we studied effects of genistein (trihydroxyisoflavone) on a HD cellular model consisting of HEK-293 cells transfected with a plasmid bearing mutated HTT gene. Both level of mutated huntingtin and number of aggregates were significantly decreased in genistein-treated HD cell model. This led to increased viability of the cells. Autophagy was up-regulated while inhibition of lysosomal functions by chloroquine impaired the genistein-mediated degradation of the mutated huntingtin aggregates. Hence, we conclude that through stimulating autophagy, genistein removes the major pathogenic factor of HD. Prolonged induction of autophagy was suspected previously to be risky for patients due to putative adverse effects; however, genistein has been demonstrated recently to be safe and suitable for long-term therapies even at doses as high as 150 mg/kg/day. Therefore, results presented in this report provide a basis for the use of genistein in further studies on development of the potential treatment of HD.

Aronin, N., & DiFiglia, M. (2014). Huntingtin-lowering strategies in Huntington’s disease: Antisense oligonucleotides, small RNAs, and gene editing. Movement Disorders, 29, 1455–1461.CrossRefPubMed

Bañez-Coronel, M., Ayhan, F., Tarabochia, A. D., Zu, T., Perez, B. A., Tusi, S. K., et al. (2015). RAN translation in Huntington disease. Neuron, 88, 667–677.CrossRefPubMedPubMedCentral

Bennett, E. J., Shaler, T. A., Woodman, B., Ryu, K. Y., Zaitseva, T. S., Becker, C. H., et al. (2007). Global changes to the ubiquitin system in Huntington’s disease. Nature, 448, 704–708.CrossRefPubMed

Bhutani, N., Venkatraman, P., & Goldberg, A. L. (2007). Puromycin-sensitive aminopeptidase is the major peptidase responsible for digesting polyglutamine sequences released by proteasomes during protein degradation. EMBO Journal, 26, 1385–1396.CrossRefPubMedPubMedCentral

de Ruijter, J., Valstar, M. J., Narajczyk, M., Wegrzyn, G., Kulik, W., Ijlst, L., et al. (2012). Genistein in Sanfilippo disease: A randomized controlled crossover trial. Annals of Neurology, 71, 110–120.CrossRefPubMed

Finkbeiner, S., & Mitra, S. (2008). The ubiquitin-proteasome pathway in Huntington’s disease. Scientific World Journal, 8, 421–433.CrossRefPubMedPubMedCentral

Galka-Marciniak, P., Urbanek, M. O., & Krzyzosiak, W. J. (2012). Triplet repeats in transcripts: Structural insights into RNA toxicity. Biological Chemistry, 393, 1299–1315.CrossRefPubMed

Gil, J. M., & Rego, A. C. (2008). Mechanisms of neurodegeneration on Huntington’s disease. European Journal of Neuroscience, 27, 2803–2820.CrossRefPubMed

Goloubinoff, P. (2016). Mechanisms of protein homeostasis in health, aging and disease. Swiss Medical Weekly, 146, w14306.PubMed

Gros, F., & Muller, S. (2014). Pharmacological regulators of autophagy and their link with modulators of lupus disease. British Journal of Pharmacology, 171, 4337–4359.CrossRefPubMedPubMedCentral

Haas, L. T., Kostylev, M. A., & Strittmatter, S. M. (2014). Therapeutic molecules and endogenous ligands regulate the interaction between brain cellular prion protein (PrPC) and metabotropic glutamate receptor 5 (mGluR5). Journal of Biological Chemistry, 289, 22477–28460.CrossRef

Jakóbkiewicz-Banecka, J., Piotrowska, E., Narajczyk, M., Barańska, S., & Wegrzyn, G. (2009). Genistein-mediated inhibition of glycosaminoglycan synthesis, which corrects storage in cells of patients suffering from mucopolysaccharidoses, acts by influencing an epidermal growth factor-dependent pathway. Journal of Biomedical Science, 16, 26.CrossRefPubMedPubMedCentral

Jana, N. R., Zemskov, E. A., Wang, G., & Nukina, N. (2001). Altered proteasomal function due to the expression of polyglutamine-expanded truncated N-terminal huntingtin induces apoptosis by caspase activation through mitochondrial cytochrome c release. Human Molecular Genetics, 10, 1049–1059.CrossRefPubMed

Kim, K. H., Dodsworth, C., Paras, A., & Burton, B. K. (2013). High dose genistein aglycone therapy is safe in patients with mucopolysaccharidoses involving the central nervous system. Molecular Genetics and Metabolism, 109, 382–385.CrossRefPubMed

Lecca, D., Nevin, D. K., Mulas, G., Casu, M. A., Diana, A., Rossi, D., et al. (2015). Neuroprotective and anti-inflammatory properties of a novel non-thiazolidinedione PPARγ agonist in vitro and in MPTP-treated mice. Neuroscience, 302, 23–35.CrossRefPubMed

Malinowska, M., Wilkinson, F. L., Bennett, W., Langford-Smith, K. J., O’Leary, H. A., Jakobkiewicz-Banecka, J., et al. (2009). Genistein reduces lysosomal storage in peripheral tissues of mucopolysaccharide IIIB mice. Molecular Genetics and Metabolism, 98, 235–242.CrossRefPubMed

Malinowska, M., Wilkinson, F. L., Langford-Smith, K. J., Langford-Smith, A., Brown, J. R., Crawford, B. E., et al. (2010). Genistein improves neuropathology and corrects behaviour in a mouse model of neurodegenerative metabolic disease. PLoS ONE, 5, e14192.CrossRefPubMedPubMedCentral

Menze, E. T., Esmat, A., Tadros, M. G., Abdel-Naim, A. B., & Khalifa, A. E. (2015). Genistein improves 3-NPA-induced memory impairment in ovariectomized rats: Impact of its antioxidant, anti-inflammatory and acetylcholinesterase modulatory properties. PLoS ONE, 10, e0117223.CrossRefPubMedPubMedCentral

Menze, E. T., Esmat, A., Tadros, M. G., Khalifa, A. E., & Abdel-Naim, A. B. (2016). Genistein improves sensorimotor gating: Mechanisms related to its neuroprotective effects on the striatum. Neuropharmacology, 105, 35–46.CrossRefPubMed

Mizushima, N., Yoshimori, T., & Levine, B. (2010). Methods in mammalian autophagy research. Cell, 140, 313–326.CrossRefPubMedPubMedCentral

Morreale, M. K. (2015). Huntington’s disease: Looking beyond the movement disorder. Advances in Psychosomatic Medicine, 34, 135–142.CrossRefPubMed

Moskot, M., Jakóbkiewicz-Banecka, J., Kloska, A., Smolińska, E., Mozolewski, P., Malinowska, M., et al. (2015a). Modulation of expression of genes involved in glycosaminoglycan metabolism and lysosome biogenesis by flavonoids. Sci Rep, 5, 9378.CrossRefPubMedPubMedCentral

Moskot, M., Jakóbkiewicz-Banecka, J., Smolińska, E., Piotrowska, E., Węgrzyn, G., & Gabig-Cimińska, M. (2015b). Effects of flavonoids on expression of genes involved in cell cycle regulation and DNA replication in human fibroblasts. Molecular and Cellular Biochemistry, 407, 97–109.CrossRefPubMedPubMedCentral

Moskot, M., Montefusco, S., Jakóbkiewicz-Banecka, J., Mozolewski, P., Węgrzyn, A., Di Bernardo, D., et al. (2014). The phytoestrogen genistein modulates lysosomal metabolism and transcription factor EB (TFEB) activation. Journal of Biological Chemistry, 289, 17054–17069.CrossRefPubMedPubMedCentral

Petrosino, S., Ahmad, A., Marcolongo, G., Esposito, E., Allarà, M., Verde, R., et al. (2015). Diacerein is a potent and selective inhibitor of palmitoylethanolamide inactivation with analgesic activity in a rat model of acute inflammatory pain. Pharmacological Research, 91, 9–14.CrossRefPubMed

Piotrowska, E., Jakóbkiewicz-Banecka, J., Barańska, S., Tylki-Szymańska, A., Czartoryska, B., Wegrzyn, A., et al. (2006). Genistein-mediated inhibition of glycosaminoglycan synthesis as a basis for gene expression-targeted isoflavone therapy for mucopolysaccharidoses. European Journal of Human Genetics, 14, 846–852.CrossRefPubMed

Pritchard, C., Mayers, A., & Baldwin, D. (2013). Changing patterns of neurological mortality in the 10 major developed countries—1979–2010. Public Health, 2013(127), 357–368.CrossRef

Pryor, W. M., Biagioli, M., Shahani, N., Swarnkar, S., Huang, W. C., Page, D. T., et al. (2014). Huntingtin promotes mTORC1 signaling in the pathogenesis of Huntington’s disease. Science Signal, 7, ra103.CrossRef

Ratovitski, T., Arbez, N., Stewart, J. C., Chighladze, E., & Ross, C. A. (2015). PRMT5- mediated symmetric arginine dimethylation is attenuated by mutant Huntingtin and is impaired in Huntington’s disease (HD). Cell Cycle, 14, 1716–1729.CrossRefPubMedPubMedCentral

Ravikumar, B., Duden, R., & Rubinsztein, D. C. (2002). Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Human Molecular Genetics, 11, 1107–1117.CrossRefPubMed

Ravikumar, B., Vacher, C., Berger, Z., Davies, J. E., Luo, S., Oroz, L. G., et al. (2004). Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nature Genetics, 36, 585–595.CrossRefPubMed

Sameni, S., Syed, A., Marsh, J. L., & Digman, M. A. (2016). The phasor-FLIM fingerprints reveal shifts from OXPHOS to enhanced glycolysis in Huntington disease. Scientific Reports, 6, 34755.CrossRefPubMedPubMedCentral

Shannon, K. M., & Fraint, A. (2015). Therapeutic advances in Huntington’s disease. Movement Disorders, 30, 1539–1546.CrossRefPubMed

Tasdemir, E., Galluzzi, L., Maiuri, M. C., Criollo, A., Vitale, I., Hangen, E., et al. (2008). Methods for assessing autophagy and autophagic cell death. Methods in Molecular Biology, 445, 29–76.CrossRefPubMed

Tsai, T. H. (2005). Concurrent measurement of unbound genistein in the blood, brain and bile of anesthetized rats using microdialysis and its pharmacokinetic application. Journal of Chromatography A, 1073, 317–322.CrossRefPubMed

Wegrzyn, G., Jakóbkiewicz-Banecka, J., Gabig-Cimińska, M., Piotrowska, E., Narajczyk, M., Kloska, A., et al. (2010). Genistein: A natural isoflavone with a potential for treatment of genetic diseases. Biochemical Society Transactions, 38, 695–701.CrossRefPubMed

Yang, Y. P., Hu, L. F., Zheng, H. F., Mao, C. J., Hu, W. D., Xiong, K. P., et al. (2013). Application and interpretation of current autophagy inhibitors and activators. Acta Pharmacologica Sinica, 34, 625–635.CrossRefPubMedPubMedCentral

Zhao, T., Hong, Y., Li, X. J., & Li, S. H. (2016). Subcellular clearance and accumulation of Huntington disease protein: A mini-review. Frontiers in Molecular Neuroscience, 9, 27.CrossRefPubMedPubMedCentral

Title: Correction of Huntington’s Disease Phenotype by Genistein-Induced Autophagy in the Cellular Model
Authors: Karolina Pierzynowska
Lidia Gaffke
Aleksandra Hać
Jagoda Mantej
Natalia Niedziałek
Joanna Brokowska
Grzegorz Węgrzyn
Publication date: 01-03-2018
Publisher: Springer US
Published in: NeuroMolecular Medicine / Issue 1/2018
Print ISSN: 1535-1084
Electronic ISSN: 1559-1174
DOI: https://doi.org/10.1007/s12017-018-8482-1

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Correction of Huntington’s Disease Phenotype by Genistein-Induced Autophagy in the Cellular Model

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