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Beneficial in vitro effect of N-acetylcysteine and coenzyme Q10 on DNA damage in neurodegenerative Niemann-Pick type C 1 disease: preliminary results

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Abstract

Niemann-Pick type C1 (NP-C1) is a lysosomal storage disease (LSD) caused by mutations in NPC1 gene that lead to defective synthesis of the respective lysosomal transporter protein and cholesterol accumulation in late endosomes/lysosomes (LE/L) compartments, as well as glycosphingolipids GM2 and GM3 in the central nervous system (CNS). Clinical presentation varies according to the age of onset and includes visceral and neurological symptoms, such as hepatosplenomegaly and psychiatric disorders. Studies have been associating the pathophysiology of NP-C1 with oxidative damage to lipids and proteins, as well as evaluating the benefits of adjuvant therapy with antioxidants for this disease. In this work, we evaluated the DNA damage in fibroblasts culture from patients with NP-C1 treated with miglustat, as well as the in vitro effect of the antioxidant compounds N-acetylcysteine (NAC) and Coenzyme Q10 (CoQ10), using the alkaline comet assay. Our preliminary results demonstrate that NP-C1 patients have increased DNA damage compared to healthy individuals and that the treatments with antioxidants can mitigate it. DNA damage may be due to an increase in reactive species since it has been described that NP-C1 patients have increased peripheral markers of damage to other biomolecules. Our study suggests that NP-C1 patients could benefit from the use of adjuvant therapy with NAC and CoQ10, which should be better evaluated in a future clinical trial.

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Acknowledgements

We would like to thank the patients and their families, as well as the medical staff of the Medical Genetics Service – HCPA for logistic and technical support in the development of this study.

Funding

This work was supported by: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/MEC-Brasil); Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq/MCTI-Brasil number 430443/2018–8); Fundo de Incentivo à Pesquisa e Eventos (FIPE/HCPA – number 2018–0648).

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Authors and Affiliations

  1. Programa de Pós-Graduação Em Ciências Farmacêuticas, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil

    Tatiane G. Hammerschmidt & Carmen R. Vargas

  2. Serviço de Genética Médica, HCPA, Rua Ramiro Barcelos, 2350, Porto Alegre, RS, CEP 90035-003, Brazil

    Gilian B. Guerreiro, Rejane G. Kessler, Roberto Giugliani & Carmen R. Vargas

  3. Grupo Hospitalar Conceição, Porto Alegre, Brazil

    Bruna Donida

  4. Laboratório de Genética Toxicológica, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil

    Marco Raabe, Matheus B. Ferro & Dinara J. Moura

Authors
  1. Tatiane G. Hammerschmidt
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  2. Gilian B. Guerreiro
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  3. Bruna Donida
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  4. Marco Raabe
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  5. Rejane G. Kessler
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  7. Dinara J. Moura
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  8. Roberto Giugliani
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  9. Carmen R. Vargas
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Contributions

TGH and CRV contributed to the study conception and design. Material preparation, data collection, and analysis were performed by TGH, BD, MR, RK, and MBF. RG, DJM, and CRV supervised the work. The first draft of the manuscript was written by TGH and GBG, as well as revised by CRV. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Tatiane G. Hammerschmidt or Carmen R. Vargas.

Ethics declarations

Ethical approval

We performed this study in line with the principles of the Declaration of Helsinki and the project was approved by the Research Ethics Committee of the Hospital de Clínicas de Porto Alegre (CEP/HCPA) under number 2018–0648.

Consent to participate

Informed consent was obtained from all individual participants, or legal guardians, included in the study.

Competing interests

RG received speaker honoraria, travel grants, educational grants, and/or investigator fees from Actelion, Amicus, Armagen, BioMarin, Inventiva, JCR Pharmaceuticals, Lysogene, RegenxBio, Sangamo, Sanofi-Genzyme, Takeda, Sobi and Ultragenyx. All other authors declare that they have no conflict of interest.

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Hammerschmidt, T.G., Guerreiro, G.B., Donida, B. et al. Beneficial in vitro effect of N-acetylcysteine and coenzyme Q10 on DNA damage in neurodegenerative Niemann-Pick type C 1 disease: preliminary results. Naunyn-Schmiedeberg's Arch Pharmacol 396, 1563–1569 (2023). https://doi.org/10.1007/s00210-023-02423-7

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