Genistein reduces lysosomal storage in peripheral tissues of mucopolysaccharide IIIB mice

Malinowska, Marcelina; Wilkinson, Fiona L.; Bennett, Bill; Langford-Smith, Kia; O’Leary, Helen; Jakóbkiewicz‐Banecka, Joanna; Wynn, Robert F.; Wraith, J. E.; Węgrzyn, Grzegorz; Bigger, Brian

doi:10.1016/j.ymgme.2009.06.013

Cited by 95 publications

(94 citation statements)

References 29 publications

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“…Some other flavonoids were also able to decrease GAG storage in MPS IIIA, IIIB, and VII cells (Arfi et al 2010;Piotrowska et al 2010;Kloska et al 2011). Similar to rhodamine B, genistein caused a marked improvement in treated MPS IIIB mice, particularly in decreasing GAG storage in various organs (Malinowska et al 2009) and in correction of otherwise severely changed behavior (Malinowska et al 2010). The same tendency of improvement was observed in MPS II mice (Friso et al 2010).…”

Section: Efficacy Of Srt In In Vitro Studies Experiments With Animalmentioning

confidence: 67%

“…Genistein was found to interfere with this pathway by inhibiting phosphorylation of EGFR (Jakobkiewicz-Banecka et al 2009). Therefore, the potential therapy based on the use of genistein as an inhibitor of the EGF-mediated signal transduction pathway has been named 'gene expressiontargeted isoflavone therapy' (GET IT) (JakobkiewiczBanecka et al 2009;Malinowska et al 2009;Piotrowska et al 2011).…”

Section: Substrate Reduction Therapies (Srps) For Mpsmentioning

confidence: 99%

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Putative Biological Mechanisms of Efficiency of Substrate Reduction Therapies for Mucopolysaccharidoses

Banecka-Majkutewicz

Jakóbkiewicz‐Banecka

Gabig-Cimińska

et al. 2012

Arch. Immunol. Ther. Exp.

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Mucopolysaccharidoses (MPS) are inherited metabolic diseases caused by mutations in genes coding for lysosomal enzymes involved in the degradation of glycosaminoglycans (GAGs). Dysfunction of any of these enzymes results in the accumulation of GAGs, which leads to severe clinical symptoms and significantly shortened life span. Several kinds of therapies have been proposed to treat MPS, including bone marrow or stem cell transplantation, enzyme replacement therapy, and gene therapy. Another option is substrate reduction therapy (SRT), in which synthesis of GAGs is inhibited. Recent studies employing in vitro and animal models suggested that this therapy may be efficient in decreasing levels of GAGs in MPS cells, including those bearing two null alleles of the affected gene. Results of behavioral tests in animals as well as some preliminary clinical observations with pediatric patients corroborated the suggestions about possible efficacy of SRT in MPS treatment, including brain functions. Efficient reduction of GAG levels in MPS cells homozygous for null mutations may be intriguing in the commonly accepted scheme of SRT mode of action. In this paper, we propose an explanation of this phenomenon, based on already known facts. Thus, we suggest that SRT may lead to reduction of GAG levels in MPS cells due to inhibition of efficiency of GAG synthesis combined with (a) any readthrough of the stop codon, (b) dilution of already accumulated GAGs due to cell growth followed by cell divisions, and (c) action of endoglycosidases degrading GAGs, e.g., heparanase, in combination with functional GAG-specific hydrolases.

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Section: Efficacy Of Srt In In Vitro Studies Experiments With Animalmentioning

confidence: 67%

Section: Substrate Reduction Therapies (Srps) For Mpsmentioning

confidence: 99%

Putative Biological Mechanisms of Efficiency of Substrate Reduction Therapies for Mucopolysaccharidoses

Banecka-Majkutewicz

Jakóbkiewicz‐Banecka

Gabig-Cimińska

et al. 2012

Arch. Immunol. Ther. Exp.

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“…Oral administration of trehalose, a known pharmacological enhancer of autophagy, increases the life span and normalizes several behavioral and neuropathological features of MPS IIIB mice, most notably rescuing their retinal degeneration. Because no disease-modifying therapies are currently available for MPS IIIB or related disorders, this study establishes a viable new approach to pharmacotherapy that could be tested either alone or in combination with other approaches under development [5,12–15,52]. …”

Section: Discussionmentioning

confidence: 99%

“…Longer-term studies will be needed to investigate the safety and effectiveness of these approaches. Other proposed treatments, including substrate reduction and use of anti-inflammatory reagents, can contribute to mitigating aspects of MPS pathology [12,52,71]. Because of its exceptionally good toxicological profile [72,73], trehalose might be safely used in combination therapies to investigate its additive or synergistic effects with other therapeutics.…”

Section: Discussionmentioning

confidence: 99%

Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency

et al. 2018

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The accumulation of undegraded molecular material leads to progressive neurodegeneration in a number of lysosomal storage disorders (LSDs) that are caused by functional deficiencies of lysosomal hydrolases. To determine whether inducing macroautophagy/autophagy via small-molecule therapy would be effective for neuropathic LSDs due to enzyme deficiency, we treated a mouse model of mucopolysaccharidosis IIIB (MPS IIIB), a storage disorder caused by deficiency of the enzyme NAGLU (alpha-N-acetylglucosaminidase [Sanfilippo disease IIIB]), with the autophagy-inducing compound trehalose. Treated naglu–/ – mice lived longer, displayed less hyperactivity and anxiety, retained their vision (and retinal photoreceptors), and showed reduced inflammation in the brain and retina. Treated mice also showed improved clearance of autophagic vacuoles in neuronal and glial cells, accompanied by activation of the TFEB transcriptional network that controls lysosomal biogenesis and autophagic flux. Therefore, small-molecule-induced autophagy enhancement can improve the neurological symptoms associated with a lysosomal enzyme deficiency and could provide a viable therapeutic approach to neuropathic LSDs.Abbreviations: ANOVA: analysis of variance; Atg7: autophagy related 7; AV: autophagic vacuoles; CD68: cd68 antigen; ERG: electroretinogram; ERT: enzyme replacement therapy; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFAP: glial fibrillary acidic protein; GNAT2: guanine nucleotide binding protein, alpha transducing 2; HSCT: hematopoietic stem cell transplantation; INL: inner nuclear layer; LC3: microtubule-associated protein 1 light chain 3 alpha; MPS: mucopolysaccharidoses; NAGLU: alpha-N-acetylglucosaminidase (Sanfilippo disease IIIB); ONL: outer nuclear layer; PBS: phosphate-buffered saline; PRKCA/PKCα: protein kinase C, alpha; S1BF: somatosensory cortex; SQSTM1: sequestosome 1; TEM: transmission electron microscopy; TFEB: transcription factor EB; VMP/VPL: ventral posterior nuclei of the thalamus

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“…For the genistein-fed group, genistein aglycone (kind gift from Axcentua) was added to the diet in a concentration of 0.1% (w/w). Assuming a food intake of 0.16 g food per gram of body weight per day, this diet results in a dose of 160 mg/kg/day, which is similar to other studies on the effects of a high dose of genistein in MPS mice (Malinowska et al 2009(Malinowska et al , 2010. One week before weaning, mice received the soy-free diet.…”

Section: Animalsmentioning

confidence: 92%

Adverse Effects of Genistein in a Mucopolysaccharidosis Type I Mouse Model

et al. 2015

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Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder characterized by diminished degradation of the glycosaminoglycans heparan sulfate (HS) and dermatan sulfate (DS). Patients present with a variety of symptoms, including severe skeletal disease. Current therapeutic strategies have only limited effects on bone disease. The isoflavone genistein has been studied as a potential therapy for the mucopolysaccharidoses because of its putative ability to inhibit GAG synthesis and subsequent accumulation. Cell, animal, and clinical studies, however, showed variable outcomes. To determine the effects of genistein on MPS I-related bone disease, wild-type (WT) and MPS I mice were fed a genistein-supplemented diet (corresponding to a dose of approximately 160 mg/kg/day) for 8 weeks. HS and DS levels in bone and plasma remained unchanged after genistein supplementation, while liver HS levels were decreased in genistein-fed MPS I mice as compared to untreated MPS I mice. Unexpectedly, genistein-fed mice exhibited significantly decreased body length and femur length. In addition, 60% of genistein-fed MPS I mice developed a scrotal hernia and/or scrotal hydrocele, manifestations ,which were absent in WT or untreated MPS I mice. In contrast to studies in MPS III mice, our study in MPS I mice demonstraes no beneficial but even potential adverse effects of genistein supplementation. Our results urge for a cautious approach on the use of genistein, at least in patients with MPS I.

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Genistein reduces lysosomal storage in peripheral tissues of mucopolysaccharide IIIB mice

Cited by 95 publications

References 29 publications

Putative Biological Mechanisms of Efficiency of Substrate Reduction Therapies for Mucopolysaccharidoses

Putative Biological Mechanisms of Efficiency of Substrate Reduction Therapies for Mucopolysaccharidoses

Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency

Adverse Effects of Genistein in a Mucopolysaccharidosis Type I Mouse Model

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