Persistent NRG1 type III overexpression in spinal motor neurons has no therapeutic effect on ALS‑related pathology in SOD1G93A mice

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting upper and lower motor neurons (MNs). Neuregulin-1 (NRG1) is a pleiotropic growth factor that has been shown to be potentially valuable for ALS when supplemented by means of viral-mediated gene therapy. However,...

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Bibliographic Details
Authors: Hernández i Estanyol, Sara, Salvany, Sara, Casanovas i Llorens, Anna, Piedrafita Llorens, Lídia, Soto-Bernardini, María Clara, Tarabal Mostazo, Olga, Blasco Carmona, Alba, Gras Artells, Sílvia, Gatius Puchercós, Alaó, Schwab, Markus H., Calderó i Pardo, Jordi, Esquerda Colell, Josep
Format: article
Status:Published version
Publication Date:2023
Country:España
Institution:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repository:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10459.1/464039
Online Access:https://doi.org/10.1007/s13311-023-01424-x
https://hdl.handle.net/10459.1/464039
Access Level:Open access
Keyword:Amyotrophic lateral sclerosis
Neuregulin-1
motor neuron
SOD1
Therapy
ALS
Neuregulin
NRG1
Motor neuron
Description
Summary:Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting upper and lower motor neurons (MNs). Neuregulin-1 (NRG1) is a pleiotropic growth factor that has been shown to be potentially valuable for ALS when supplemented by means of viral-mediated gene therapy. However, these results are inconsistent with other reports. An alternative approach for investigating the therapeutic impact of NRG1 on ALS is the use of transgenic mouse lines with genetically defined NRG1 overexpression. Here, we took advantage of a mouse line with NRG1 type III overexpression in spinal cord α motor neurons (MN) to determine the impact of steadily enhanced NRG1 signalling on mutant superoxide dismutase 1 (SOD1)-induced disease. The phenotype of SOD1G93A-NRG1 double transgenic mice was analysed in detail, including neuropathology and extensive behavioural testing. At least 3 animals per condition and sex were histopathologically assessed, and a minimum of 10 mice per condition and sex were clinically evaluated. The accumulation of misfolded SOD1 (mfSOD1), MN degeneration, and a glia-mediated neuroinflammatory response are pathological hallmarks of ALS progression in SOD1G93A mice. None of these aspects was significantly improved when examined in double transgenic NRG1- SOD1G93A mice. In addition, behavioural testing revealed that NRG1 type III overexpression did not affect the survival of SOD1G93A mice but accelerated disease onset and worsened the motor phenotype.

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