The heat shock/stress response of motor neurons : a potential therapeutic target in amyotrophic lateral sclerosis

Heat shock proteins (HSPs) play important roles in the maintenance and preservation of cellular homeostasis. Since previous findings demonstrated a neuroprotective role of the stress-inducible Hsp70 in an in vitro model of the neurodegenerative disease, amyotrophic lateral sclerosis (ALS) (Bruening et al., 1999), the objectives of this research was to study the endogenous heat shock response of motor neurons exposed to various stresses and to determine if known pharmacological inducers of HSPs can enhance the stress response of these cells. Neither heat shock nor glutamate excitotoxicity induced Hsp70 in motor neurons. In primary spinal cord cultures, expression of Cu/Zn superoxide dismutase (SOD-1) with mutations responsible for familial ALS also failed to result in Hsp70 induction, nor was Hsp70 expressed in spinal motor neurons of mutant SOD-1 (mSOD) transgenic mice or patients with sporadic or familial ALS. The lack of a strong heat shock response was associated with an inability to activate the main stress-sensing transcription factor, heat shock transcription factor-1 (HSF1). Overexpression of an activated form of HSF1, but not wildtype HSF1, in cultured motor neurons resulted in significant protection from mutant SOD-1 toxicity, which was accompanied by increased expression of Hsp70, Hsp40, and to a lesser degree, Hsp25. The effects of two nonsteroidal anti-inflammatory drugs, sodium salicylate, shown in cell lines to increase HSF1 binding to promoters of HSP genes (Jurivich et al., 1992), and niflumic acid, a preferential COX-2 inhibitor, on the heat shock response of motor neurons were assessed. Both drugs lowered the temperature threshold for induction of Hsp70 in glia and non-neuronal cells, but not in motor neurons. Concomitantly, neither drug prevented mSOD-mediated motor neuron death. Pyrrolidine dithiocarbamate (PDTC), previously shown to upregulate Hsp70 in cell lines through increased DNA binding and activation of HSF1 (D