| Description: |
Amyotrophic lateral sclerosis (ALS) is a multifactorial disease characterized by the progressive degeneration of motor neurons (MN) and muscle paralysis. Despite current treatments, patients survive less than 3–5 years after the initial diagnosis. Most ALS cases are sporadic (sALS), and only 5-10% have a familial origin (fALS). Among the latter, about 20% express a dominant mutant form of the Cu, Zn superoxide dismutase (SOD1) (Rothstein, 2009). Transgenic mice expressing a mutant SOD1 develop MN pathology, with muscle denervation and weakness similar to ALS patients (Fischer et al., 2004). Many evidence demonstrate that ALS is non-cell autonomous, with multiple co-players involved in disease progression (Robberecht et al, 2013). In particular, signals from both glial cells and muscles initiate and sustain MN degeneration (Boillée et al., 2006; Dobrowolny et al, 2008). Recent studies described a critical role for microglia in amyotrophic lateral sclerosis (ALS), where these CNS-resident immune cells participate in the establishment of an inflammatory microenvironment that contributes to motor neuron degeneration. Understanding the mechanisms leading to microglia activation in ALS could help to identify specific molecular pathways which could be targeted to reduce or delay motor neuron degeneration and muscle paralysis in patients. The intermediate-conductance calciumactivated potassium channel KCa3.1 has been reported to modulate the “pro-inflammatory” phenotype of microglia in different pathological conditions. We here investigated the effects of blocking KCa3.1 activity in the hSOD1G93AALS mouse model, which recapitulates many features of the human disease. We report that treatment of hSOD1G93A mice with a selective KCa3.1 inhibitor, 1-[(2-chlorophenyl) diphenylmethyl]-1H-pyrazole (TRAM-34), attenuates the “pro-inflammatory” phenotype of microglia in the spinal cord, reduces motor neuron death, delays onset of muscle weakness, and increases survival. Specifically, inhibition of KCa3.1 channels slowed muscle ... |