Changes in expressions of genes involved in the regulation of cellular processes in mucopolysaccharidoses as assessed by fibroblast culture-based transcriptomic analyses

Gaffke, Lidia; Pierzynowska, Karolina; Krzelowska, Karolina; Piotrowska, Ewa; Węgrzyn, Grzegorz

doi:10.1007/s11011-020-00614-2

Cited by 13 publications

(16 citation statements)

References 22 publications

(35 reference statements)

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“…This may indicate that the pathogenesis of LSDs is not limited to the primary cause—accumulation of the storage material. Such a hypothesis can be corroborated by recently published results demonstrating dysregulation of expression of hundreds of genes, coding for proteins involved in various cellular processes, in fibroblasts derived from patients suffering from mucopolysaccharidoses [ 51 , 106 , 107 , 108 , 109 , 110 , 111 ].…”

Section: Ferroptosis Disorders As a Mechanism For Pathogenesis Of mentioning

confidence: 62%

Ferroptosis and Its Modulation by Autophagy in Light of the Pathogenesis of Lysosomal Storage Diseases

Pierzynowska

Rintz

Gaffke

et al. 2021

Cells

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Ferroptosis is one of the recently described types of cell death which is dependent on many factors, including the accumulation of iron and lipid peroxidation. Its induction requires various signaling pathways. Recent discovery of ferroptosis induction pathways stimulated by autophagy, so called autophagy-dependent ferroptosis, put our attention on the role of ferroptosis in lysosomal storage diseases (LSD). Lysosome dysfunction, observed in these diseases, may influence ferroptosis efficiency, with as yet unknown consequences for the function of cells, tissues, and organisms, due to the effects of ferroptosis on physiological and pathological metabolic processes. Modulation of levels of ferrous ions and enhanced oxidative stress, which are primary markers of ferroptosis, are often described as processes associated with the pathology of LSD. Inhibition of autophagy flux and resultant accumulation of autophagosomes in neuronopathic LSD may induce autophagy-dependent ferroptosis, indicating a considerable contribution of this process in neurodegeneration. In this review article, we describe molecular mechanisms of ferroptosis in light of LSD, underlining the modulation of levels of ferroptosis markers in these diseases. Furthermore, we propose a hypothesis about the possible involvement of autophagy-dependent ferroptosis in these disorders.

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Section: Ferroptosis Disorders As a Mechanism For Pathogenesis Of mentioning

confidence: 62%

Ferroptosis and Its Modulation by Autophagy in Light of the Pathogenesis of Lysosomal Storage Diseases

Pierzynowska

Rintz

Gaffke

et al. 2021

Cells

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“…32 Such global changes in levels of transcripts and proteins encoded by them result in dysmorphology and dysfunctions of different cellular organelles (like nucleus, mitochondria, endoplasmic reticulum, Golgi apparatus), 33 as well as abnormalities in various cellular processes. 34 Among them, apoptosis, 35 cell activation, 36 proteasomal degradation, 37 homeostasis of different ions (especially Ca 2+ , Fe 2+ and Zn 2+ ), 38 signal transduction, 39 and cell cycle, 40 are especially strongly affected. It was suggested that even behavioral disorders appearing in Sanfilippo disease and some other MPS types might be partially caused by disturbed regulation of expression of specific genes.…”

Section: Complexity Of Sanfilippo Disease Pathomechanismsmentioning

confidence: 99%

Sanfilippo Syndrome: Optimizing Care with a Multidisciplinary Approach

Cyske¹,

Anikiej-Wiczenbach²,

Wiśniewska³

et al. 2022

JMDH

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Sanfilippo syndrome, or mucopolysaccharidosis type III (MPS III), is a disease grouping five genetic disorders, four of them occurring in humans and one known to date only in a mouse model. In every subtype of MPS III (designed A, B, C, D or E), a lack or drastically decreased activity of an enzyme involved in the degradation of heparan sulfate (HS) (a compound from the group of glycosaminoglycans (GAGs)) arises from a genetic defect. This leads to primary accumulation of HS, and secondary storage of other compounds, combined with changes in expressions of hundreds of genes and many defects in organelles and various biochemical processes in the cell. As a result, dysfunctions of tissues and organs occur, leading to severe symptoms in patients. Although changes in somatic organs are considerable, the central nervous system is especially severely affected, and neurological, cognitive and behavioral disorders are the most significant changes, making the disease enormously burdensome for patients and their families. In the light of the current lack of any registered therapy for Sanfilippo syndrome (despite various attempts of many research groups to develop effective treatment, still no specific drug or procedure is available for MPS III), optimizing care with a multidisciplinary approach is crucial for managing this disease and making quality of patients' life passable. This includes efforts to make/organize (i) accurate diagnosis as early as possible (which is not easy due to various possible misdiagnosis events caused by similarity of MPS III symptoms to those of other diseases and variability of patients), (ii) optimized symptomatic treatment (which is challenging because of complexity of symptoms and often untypical responses of MPS III patients to various drugs), and (iii) psychological care (for both patients and family members and/or caregivers). In this review article, we focus on these approaches, summarizing and discussing them.

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“…Severe neurodegeneration is a major obstacle in the development of an effective therapy for this disease, as it is challenging to find an efficient way to deliver potential drugs, especially large molecules, to the brain [6]. Moreover, recent studies have indicated that although HS storage is the major pathomechanism of the disease, secondary processes, including the dysregulated expression of hundreds of genes encoding proteins involved in the structures and functions of various cellular organelles, as well as different cellular processes (such as metabolic processes, cell communication, signal transduction, cell development, movement of subcellular components, and the cell cycle), may significantly influence the pathomechanisms of Sanfilippo disease, hindering the development of effective therapies [11][12][13][14]. Recent failures in the clinical improvements of MPS III patients participating in clinical trials with different kinds of therapies, such as gene therapy [15], enzyme replacement therapy [16,17], and substrate reduction therapy [18], have confirmed the great challenge to finding an effective therapy for Sanfilippo disease [19].…”

Section: Introductionmentioning

confidence: 99%

Activities of (Poly)phenolic Antioxidants and Other Natural Autophagy Modulators in the Treatment of Sanfilippo Disease: Remarkable Efficacy of Resveratrol in Cellular and Animal Models

et al. 2023

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Sanfilippo disease, caused by mutations in the genes encoding heparan sulfate (HS) (a glycosaminoglycan; GAG) degradation enzymes, is a mucopolysaccharidosis (MPS), which is also known as MPS type III, and is characterized by subtypes A, B, C, and D, depending on identity of the dysfunctional enzyme. The lack of activity or low residual activity of an HS-degrading enzyme leads to excess HS in the cells, impairing the functions of different types of cells, including neurons. The disease usually leads to serious psychomotor dysfunction and death before adulthood. In this work, we show that the use of molecules known as dietary (poly)phenolic antioxidants and other natural compounds known as autophagy activators (genistein, capsaicin, curcumin, resveratrol, trehalose, and calcitriol) leads to accelerated degradation of accumulated HS in the fibroblasts of all subtypes of MPS III. Both the cytotoxicity tests we performed and the available literature data indicated that the use of selected autophagy inducers was safe. Since it showed the highest effectivity in cellular models, resveratrol efficacy was tested in experiments with a mouse model of MPS IIIB. Urinary GAG levels were normalized in MPS IIIB mice treated with 50 mg/kg/day resveratrol for 12 weeks or longer. Behavioral tests indicated complete correction of hyperactivity and anxiety in these animals. Biochemical analyses indicated that administration of resveratrol caused autophagy stimulation through an mTOR-independent pathway in the brains and livers of the MPS IIIB mice. These results indicate the potential use of resveratrol (and possibly other autophagy stimulators) in the treatment of Sanfilippo disease.

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Changes in expressions of genes involved in the regulation of cellular processes in mucopolysaccharidoses as assessed by fibroblast culture-based transcriptomic analyses

Cited by 13 publications

References 22 publications

Ferroptosis and Its Modulation by Autophagy in Light of the Pathogenesis of Lysosomal Storage Diseases

Ferroptosis and Its Modulation by Autophagy in Light of the Pathogenesis of Lysosomal Storage Diseases

Sanfilippo Syndrome: Optimizing Care with a Multidisciplinary Approach

Activities of (Poly)phenolic Antioxidants and Other Natural Autophagy Modulators in the Treatment of Sanfilippo Disease: Remarkable Efficacy of Resveratrol in Cellular and Animal Models

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