Chaperone Therapy for GM2 Gangliosidosis: Effects of Pyrimethamine on β-Hexosaminidase Activity in Sandhoff Fibroblasts

Chiricozzi, Elena; Niemir, Natalia; Aureli, Massimo; Magini, Alessandro; Loberto, Nicoletta; Prinetti, Alessandro; Bassi, Rajiv; Polchi, Alice; Emiliani, Carla; Caillaud, Catherine; Sonnino, Sandro

doi:10.1007/s12035-013-8605-5

Cited by 33 publications

(21 citation statements)

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“…It is mainly found in a higher frequency in Portugal [45, 48-50, 52, 54, 55]. It found in HEXA gene and affect the active site residue in the alpha subunit of Hex A enzyme, affecting its structure and subsequently its function by inactivating it leading to Tay-Sachs disease [45,47,49,51,[54][55][56]. And that is confirming this study outcome to be a damaging SNP.…”

Section: Discussionsupporting

confidence: 74%

Thirty two novel nsSNPs May effect onHEXAprotein Leading to Tay-Sachs disease (TSD) Using a Computational Approach

Ta¹,

Fadul²,

Dn³

et al. 2019

Preprint

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Background: Genetic polymorphisms in the HEXA gene are associated with a neurodegenerative disorder called Tay-Sachs disease (TSD) (GM2 gangliosidosis type 1). This study aimed to predict the possible pathogenic SNPs of this gene and their impact on the protein using different bioinformatics tools. Methods: SNPs retrieved from the NCBI database were analyzed using several bioinformatics tools. The different algorithms collectively predicted the effect of single nucleotide substitution on both structure and function of the hexosaminidase A protein.Results: Fifty nine mutations were found to be highly damaging to the structure and function of the HEXA gene protein.Conclusion: According to this study, thirty two novel nsSNP in HEXA are predicted to have possible role in Tay-Saches Disease using different bioinformatics tools. Our findings could help in genetic study and diagnosis of Tay-Saches Disease.Keywords: Tay-Sachs disease (TSD), GM2 gangliosidosis, hexosaminidase A, HEXA, a neurodegenerative disorder, bioinformatics, single nucleotide polymorphisms (SNPs), computational, insilico. ganglioside which is caused by mutations in HEXA gene the highest concentration of GM2 ganglioside found in neuronal cells and they are the main glycolipids of neuronal cell's plasma membranes responsible of the normal cellular activities. Patients with HexA deficiency suffer from GM2 ganglioside accumulates inside neural's lysosomes. Therefore, HexA deficiency primarily affects the nervous system [1,2,4,[6][7][8][9][10][11][12][13][14].According to the disease onset age, TSD is differentiated into three types which are: acute infantile, juvenile, and late-onset. Acute infantile TSD is the most common type. It causes progressive weakness and motor skills lost in the infected infants. This progression occurs between the ages of six months to three years. In addition, the infected infant progressively suffers from diminished attentiveness and an exaggerated startle response. As TSD continues to destroy the brain infant suffers from seizures, blindness, and death which usually occurs before four years of age [8,9,11,[13][14][15].The human HEXA gene [OMIM *606869] encodes the alpha subunit of the lysosomal hexosaminidase A isozyme (HexA) which is located on chromosome 15 q23-q24 and contains 14 exons. More than two hundred mutations have been reported in the HEXA gene to cause TSD and its variants. These mutations include single base substitutions, small deletion, duplications, insertions splicing alterations, complex gene rearrangement, partial large duplications, partial deletion, splicing mutations, nonsense mutations and missense mutations that lead to the disruption of transcription, translation, folding, dimerization of monomers and catalytic dysfunction of HexA protein [4,8,11,15,16].

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Section: Discussionsupporting

confidence: 74%

Thirty two novel nsSNPs May effect onHEXAprotein Leading to Tay-Sachs disease (TSD) Using a Computational Approach

Ta¹,

Fadul²,

Dn³

et al. 2019

Preprint

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“…This pattern has been shown for other lysosomal enzymes as well [Germain and Fan, ; Suzuki et al., ; Dawson et al., ; Andreotti et al., ; de Ruijter et al., ; Aguilar‐Moncayo et al., ; Clark et al., ; Boyd et al., ; Suzuki, ; Berardi et al., ; Chiricozzi et al., ]. As a result of the partitioning between ER‐retained mutant GCase, which undergoes proteasomal degradation, and the lysosomal mutant protein, which, like other lysosomal proteins undergoes lysosomal degradation, one can appreciate that when the amount of mutant GCase that undergoes lysosomal degradation is lower, the mutation is correlated with a clinically more severe phenotype [Ron and Horowitz, ].…”

Section: Cellular Dysfunction In Gaucher Diseasementioning

confidence: 67%

New Directions in Gaucher Disease

et al. 2016

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In Gaucher disease (GD), mutant lysosomal acid β-glucocerebrosidase fails to properly hydrolyze its substrate, glucosylceramide, which accumulates in the lysosomes. Due to its phenotypic heterogeneity, GD has been classified into type 1, non-neuronopathic, and types 2 and 3, the neuronopathic forms, based on the primary involvement of the central nervous system. Neuroinflammation and necroptotic death may appear in the neuronopathic forms of GD, whereas type 1 GD patients may develop Parkinson disease (PD), a prototype of protein misfolding disorders of the nervous system. PD is significantly more prevalent among GD carriers and patients than among the non-GD populations. It is apparent that the amount of mutant enzyme present in lysosomes depends on the amount of mutant enzyme recognized as correctly folded in the endoplasmic reticulum (ER) for physiologically correct transport through the Golgi apparatus to the lysosome. Mutant enzyme recognized as misfolded is retained in the ER, inducing the Unfolded Protein Response. In the current review, we present three discrete areas of interest: molecular and cellular mechanisms underlying the association between GD and PD; the clinical and genetic associations between GD and PD; and treatment options for GD. We also discuss the relevance of induced pleuripotent stem cells to the above associations.

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“…Pyrimethamine (PYR) is a PC that reached phase II clinical trials to treat such disorders. It is an FDA approved antimalarial drug that binds to the active site of dihydrofolate reductase (DHFR) enzyme (Deloron et al, 2010; Chiricozzi et al, 2014). Due to structural similarities between Hex and DHFR active sites, PYR binds to Hex active site acting as a competitive inhibitor (Bateman et al, 2011).…”

Section: Therapeutic Strategies In the Treatment Of Lsds: The Emergenmentioning

confidence: 99%

“…From two phase II clinical studies, PYR showed promising results with some mutants in SD and TSD diseases but not with all patients affected by late-onset form the disease (Clarke et al, 2011; Osher et al, 2011). There are still some concerns to be elucidated like drug side effects and pharmacokinetics in neuronal cells (Chiricozzi et al, 2014). …”

Section: Therapeutic Strategies In the Treatment Of Lsds: The Emergenmentioning

confidence: 99%

Pharmaceutical Chaperones and Proteostasis Regulators in the Therapy of Lysosomal Storage Disorders: Current Perspective and Future Promises

et al. 2017

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Different approaches have been utilized or proposed for the treatment of lysosomal storage disorders (LSDs) including enzyme replacement and hematopoietic stem cell transplant therapies, both aiming to compensate for the enzymatic loss of the underlying mutated lysosomal enzymes. However, these approaches have their own limitations and therefore the vast majority of LSDs are either still untreatable or their treatments are inadequate. Missense mutations affecting enzyme stability, folding and cellular trafficking are common in LSDs resulting often in low protein half-life, premature degradation, aggregation and retention of the mutant proteins in the endoplasmic reticulum. Small molecular weight compounds such as pharmaceutical chaperones (PCs) and proteostasis regulators have been in recent years to be promising approaches for overcoming some of these protein processing defects. These compounds are thought to enhance lysosomal enzyme activity by specific binding to the mutated enzyme or by manipulating components of the proteostasis pathways promoting protein stability, folding and trafficking and thus enhancing and restoring some of the enzymatic activity of the mutated protein in lysosomes. Multiple compounds have already been approved for clinical use to treat multiple LSDs like migalastat in the treatment of Fabry disease and others are currently under research or in clinical trials such as Ambroxol hydrochloride and Pyrimethamine. In this review, we are presenting a general overview of LSDs, their molecular and cellular bases, and focusing on recent advances on targeting and manipulation proteostasis, including the use of PCs and proteostasis regulators, as therapeutic targets for some LSDs. In addition, we present the successes, limitations and future perspectives in this field.

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Chaperone Therapy for GM2 Gangliosidosis: Effects of Pyrimethamine on β-Hexosaminidase Activity in Sandhoff Fibroblasts

Cited by 33 publications

References 50 publications

Thirty two novel nsSNPs May effect onHEXAprotein Leading to Tay-Sachs disease (TSD) Using a Computational Approach

Thirty two novel nsSNPs May effect onHEXAprotein Leading to Tay-Sachs disease (TSD) Using a Computational Approach

New Directions in Gaucher Disease

Pharmaceutical Chaperones and Proteostasis Regulators in the Therapy of Lysosomal Storage Disorders: Current Perspective and Future Promises

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