New Statement About NRF2 in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Overview

Journal Biomolecules

Publisher MDPI

Specialties Biochemistry
Molecular Biology

Date 2022 Sep 23

PMID 36139039

Authors

Isabel Lastres-Becker

Eva de Lago

Ana Martinez

Javier Fernandez-Ruiz

Affiliations

Soon will be listed here.

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are related neurodegenerative disorders displaying substantial overlay, although there are substantial differences at the molecular level. Currently, there is no effective treatment for these diseases. The transcription factor NRF2 has been postulated as a promising therapeutic target as it is capable of modulating key pathogenic events affecting cellular homeostasis. However, there is little experimental evidence on the status of this pathway in both ALS and FTD. Therefore, in this work, we wanted to carry out an exhaustive analysis of this signaling pathway in both transgenic mouse models (ALS and FTD) and human samples from patients with sporadic ALS (sALS) versus controls. In samples from patients with sALS and in the transgenic model with overexpression of TDP-43, we observed a significant increase in the NRF2/ARE pathway in the motor cortex and the spinal cord, indicating that NRF2 antioxidant signaling was being induced, but it was not enough to reach cellular homeostasis. On the other hand, in the transgenic FTD model with overexpression of the TDP-43 protein in forebrain neurons, a significantly decreased expression of NQO1 in the prefrontal cortex was seen, which cannot be attributed to alterations in the NRF2 pathway. Our results show that NRF2 signature is differently affected for ALS and FTD.

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