Regular ArticleFluoxetine is neuroprotective in slow-channel congenital myasthenic syndrome

- First demonstration at the synaptic level of neuroprotection of a genetic degenerative disease
- Confirms more than functional improvement, i.e., neuroprotection in a human disease model
- Two distinct genetic lines gave virtually identical results.
- The model serves as a preclinical pipeline for short and long term testing of potential treatments.

The slow-channel congenital myasthenic syndrome (SCS) is an inherited neurodegenerative disease that caused mutations in the acetylcholine receptor (AChR) affecting neuromuscular transmission. Leaky AChRs lead to Ca2 + overload and degeneration of the neuromuscular junction (NMJ) attributed to activation of cysteine proteases and apoptotic changes of synaptic nuclei. Here we use transgenic mouse models expressing two different mutations found in SCS to demonstrate that inhibition of prolonged opening of mutant AChRs using fluoxetine not only improves motor performance and neuromuscular transmission but also prevents Ca2 + overload, the activation of cysteine proteases, calpain, caspase-3 and 9 at endplates, and as a consequence, reduces subsynaptic DNA damage at endplates, suggesting a long term benefit to therapy. These studies suggest that prolonged treatment of SCS patients with open ion channel blockers that preferentially block mutant AChRs is neuroprotective.