Abstract
Inherited metabolic disorders (IMDs) are rare genetic conditions that affect multiple organs, predominantly the central nervous system. Since treatment for a large number of IMDs is limited, there is an urgent need to find novel therapeutical targets. Nuclear factor erythroid-2-related factor 2 (Nrf2) is a transcription factor that has a key role in controlling the intracellular redox environment by regulating the expression of antioxidant enzymes and several important genes related to redox homeostasis. Considering that oxidative stress along with antioxidant system alterations is a mechanism involved in the neuropathophysiology of many IMDs, this review focuses on the current knowledge about Nrf2 signaling dysregulation observed in this group of disorders characterized by neurological dysfunction. We review here Nrf2 signaling alterations observed in X-linked adrenoleukodystrophy, glutaric acidemia type I, hyperhomocysteinemia, and Friedreich’s ataxia. Additionally, beneficial effects of different Nrf2 activators are shown, identifying a promising target for treatment of patients with these disorders. We expect that this article stimulates research into the investigation of Nrf2 pathway involvement in IMDs and the use of potential pharmacological modulators of this transcription factor to counteract oxidative stress and exert neuroprotection.
Highlights
Inherited metabolic disorders (IMDs) are rare genetic conditions that affect multiple organs, predominantly the central nervous system
Considering that oxidative stress along with antioxidant system alterations is a mechanism involved in the neuropathophysiology of many IMDs, this review focuses on the current knowledge about Nuclear factor erythroid-2-related factor 2 (Nrf2) signaling dysregulation observed in this group of disorders characterized by neurological dysfunction
It was found that NF-κB expression was increased whereas heme oxygenase-1 (HO-1) content was decreased in the striatum of these animals (Amaral et al, 2019). These findings demonstrated that Nrf2 signaling and redox homeostasis are altered in brain of Gcdh−/− mice submitted to Lys overload, effects that are induced at least partially by increased brain concentrations of glutaric acid (GA) and 3-hydroxygluric acid (3HGA) derived from high Lys levels (Wajner, 2019)
Summary
Received: 28 September 2021 Accepted: 05 November 2021 Published: 26 November 2021. Citation: Seminotti B, Grings M, Tucci P, Leipnitz G and Saso L (2021) Nuclear Factor Erythroid-2-Related Factor 2. Signaling in the Neuropathophysiology of Inherited Metabolic Disorders. Inherited metabolic disorders (IMDs) are rare genetic conditions that affect multiple organs, predominantly the central nervous system. Considering that oxidative stress along with antioxidant system alterations is a mechanism involved in the neuropathophysiology of many IMDs, this review focuses on the current knowledge about Nrf signaling dysregulation observed in this group of disorders characterized by neurological dysfunction. We review here Nrf signaling alterations observed in X-linked adrenoleukodystrophy, glutaric acidemia type I, hyperhomocysteinemia, and Friedreich’s ataxia. Beneficial effects of different Nrf activators are shown, identifying a promising target for treatment of patients with these disorders. We expect that this article stimulates research into the investigation of Nrf pathway involvement in IMDs and the use of potential pharmacological modulators of this transcription factor to counteract oxidative stress and exert neuroprotection
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
