Argininosuccinate neurotoxicity and prevention by creatine in argininosuccinate lyase deficiency: an in vitro study in rat 3D organotypic brain cell cultures.

Diez-Fernandez, Carmen; Hertig, Damian; Loup, Marc; Diserens, Gaëlle; Henry, Hugues; Vermathen, Peter; Nuoffer, Jean-Marc; Häberle, Johannes; Braissant, Olivier (2019). Argininosuccinate neurotoxicity and prevention by creatine in argininosuccinate lyase deficiency: an in vitro study in rat 3D organotypic brain cell cultures. (In Press). Journal of inherited metabolic disease Wiley 10.1002/jimd.12090

[img] Text
Diez-Fernandez_et_al-2019-Journal_of_Inherited_Metabolic_Disease.pdf - Accepted Version
Restricted to registered users only until 26 March 2020.
Available under License Publisher holds Copyright.

Download (3MB) | Request a copy
[img] Text
Diez-Fernandez_et_al-2019-Journal_of_Inherited_Metabolic_Disease.pdf - Published Version
Restricted to registered users only
Available under License Publisher holds Copyright.

Download (2MB) | Request a copy

The urea cycle disorder (UCD) argininosuccinate lyase (ASL) deficiency, caused by a defective ASL enzyme, exhibits a wide range of phenotypes, from life-threatening neonatal hyperammonemia to asymptomatic patients, with only the biochemical marker argininosuccinic acid (ASA) elevated in body fluids. Remarkably, even without ever suffering from hyperammonemia, patients often develop severe cognitive impairment and seizures. The goal of this study was to understand the effect on the known toxic metabolite ASA and the assumed toxic metabolite guanidinosuccinic acid (GSA) on developing brain cells, and to evaluate the potential role of creatine (Cr) supplementation, as it was described protective for brain cells exposed to ammonia. We used an in vitro model, in which we exposed 3D organotypic rat brain cell cultures in aggregates to different combinations of the metabolites of interest at two time points (representing two different developmental stages). After harvest and cryopreservation of the cell cultures, the samples were analysed mainly by metabolite analysis, immunohistochemistry and western blotting. ASA and GSA were found toxic for astrocytes and neurons. This toxicity could be reverted in vitro by Cr. As well, an anti-apoptotic effect of ASA was revealed, which could contribute to the neurotoxicity in ASL deficiency. Further studies in human ASL deficiency will be required to understand the biochemical situation in the brain of affected patients, and to investigate the impact of high or low arginine doses on brain Cr availability. In addition, clinical trials to evaluate the beneficial effect of Cr supplementation in ASL deficiency would be valuable. This article is protected by copyright. All rights reserved.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Radiology, Neuroradiology and Nuclear Medicine (DRNN) > Institute of Diagnostic, Interventional and Paediatric Radiology > DCR Magnetic Resonance Spectroscopy and Methodology (AMSM)
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Pavillon 52 > Abt. Magnetresonanz-Spektroskopie und Methodologie, AMSM

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Hertig, Damian; Diserens, Gaëlle and Vermathen, Peter

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0141-8955

Publisher:

Wiley

Language:

English

Submitter:

Maria de Fatima Henriques Bernardo

Date Deposited:

15 Jul 2019 10:52

Last Modified:

23 Oct 2019 23:18

Publisher DOI:

10.1002/jimd.12090

PubMed ID:

30907007

BORIS DOI:

10.7892/boris.130120

URI:

https://boris.unibe.ch/id/eprint/130120

Actions (login required)

Edit item Edit item
Provide Feedback