Oxidative stress and inflammation are important pathogenetic mechanisms in amyotrophic lateral sclerosis (ALS). Nuclear erythroid 2-related factor 2 (Nrf2) is a basic region leucine-zipper transcription factor that binds to the antioxidant response element, thereby regulating the expression of many genes that are involved in cellular antioxidant and anti-inflammatory defense. Under normal conditions, Nrf2 activation is inhibited by Kelch-like ECH-associated protein 1 (Keap1). We investigated the potential involvement of the Nrf2/antioxidant response element signaling pathway in the selective degeneration of motor neurons in ALS. Nrf2 and Keap1 expression was analyzed in primary motor cortex and spinal cord postmortem tissue samples from ALS patients and controls by in situ hybridization histochemistry, quantitative real-time polymerase chain reaction, immunohistochemistry, and Western blot analysis. In ALS samples, there was a reduction of Nrf2 mRNA and protein expression in neurons, whereas Keap1 mRNA expression was increased in the motor cortex. These results suggest that alterations in this signaling cascade occur in motor neurons in ALS and that they may contribute to chronic motor neuron degeneration.

Histone deacetylases (HDACs) are important regulators of gene expression and cell differentiation. The HDAC inhibitors have recently been considered as potential novel neuroprotective drugs for the treatment of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). A major limitation, however, lies in the broad spectrum of action of currently available HDAC inhibitors that may cause a variety of toxic side effects. The mRNA expression levels of the HDAC isoforms HDACs 1 to 11 have previously been characterized in rat brain but have not been studied in human tissue. Using in situ hybridization histochemistry and immunohistochemistry we assessed the distribution and expression levels of HDACs 1to 11 in postmortem ALS and control brain and spinal cord specimens (n = 6 cases each) to determine alterations in the mRNA expression pattern that could provide a basis for disease-specific therapies. We found a reduction of HDAC 11 mRNA and increased HDAC 2 levels in ALS brain and spinal cord compared with controls. A more precise knowledge of the disease-related expression pattern could lead to the development of more specific pharmacotherapeutic approaches.

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