Abstract
Nrf2 (nuclear erythroid 2-related factor 2) is a basic region leucine-zipper transcription factor which binds to the antioxidant response element (ARE) and thereby regulates the expression of a large battery of genes involved in the cellular antioxidant and anti-inflammatory defence as well as mitochondrial protection. As oxidative stress, inflammation and mitochondrial dysfunctions have been identified as important pathomechanisms in amyotrophic lateral sclerosis (ALS), this signaling cascade has gained interest both with respect to ALS pathogenesis and therapy. Nrf2 and Keap1 expressions are reduced in motor neurons in postmortem ALS tissue. Nrf2-activating compounds have shown therapeutic efficacy in the ALS mouse model and other neurodegenerative disease models. Alterations in Nrf2 and Keap1 expression and dysregulation of the Nrf2/ARE signalling program could contribute to the chronic motor neuron degeneration in ALS and other neurodegenerative diseases. Therefore, Nrf2 emerges as a key neuroprotective molecule in neurodegenerative diseases. Our recent studies strongly support that the Nrf2/ARE signalling pathway is an important mediator of neuroprotection and therefore represents a promising target for development of novel therapies against ALS, Parkinson's disease (PD), Huntington's disease (HD), and Alzheimer's disease (AD).
Highlights
Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease
Recent breakthroughs in genetics have enlarged the number of known mutations causing fALS, among them mutations in genes coding for superoxide dismutase 1 (SOD1), TAR DNA-binding protein (TARDP), fused-in sarcoma/translocation in liposarcoma (FUS/TLS), and, most recently, a repeat expansion of C9orf72, the cause of chromosome 9-linked ALS and frontotemporal lobar dementia (FTLD) [2]
Several studies have attempted to clarify the role of the Nrf2-pathway in SOD1-G93A transgenic ALS animal and in vitro models: reduced Nrf2-expression has been described in primary embryonic motor neuron cultures derived from SOD1-G93A transgenic mice
Summary
Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease. Several interdependent and interacting mechanisms have been shown to induce motor neuron damage in both fALS and sALS: excitotoxicity, aberrant RNA processing, altered axonal transport, protein aggregation, mitochondrial dysfunction, toxicity of nonneuronal (glial) cells and oxidative stress [4]. Nrf is bound to the endogenous inhibitor Kelch-like ECH associated protein (Keap1) Once activated, it translocates to the nucleus of the cell where it forms heterodimers with other transcription factors such as c-Jun and small Maf proteins (G/F/K), binds to the antioxidant response element (ARE), a regulatory enhancer region within gene promoters. Restorative effects of Nrf were reported in mice exposed to cigarette smoke [41]
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