moodle-2017-2018.calstatela.edu 1 of 20 are Introduction Amyotrophic lateral scl
ID: 254893 • Letter: M
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moodle-2017-2018.calstatela.edu 1 of 20 are Introduction Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal neurodegenerative disorder affecting motor function, with mean survival of 3 years from disease onset. Considerable progress has been made in unrav eling the genetic etiology of ALS. This led to the development of animal models that permitted significant pathobiological insights and led to tremendous efforts that have so far unfortunately failed to find a treat ment or cure for ALS (1). The treatments to slow the progression of ALS are riluzole (2) and more recently edaravone (3), but they are only modestly effective. Therefore, there is an urgent need to develop and assess new therapeutics for ALS, which remains one of the greatest challenges in neurology. Here, we consider neuromuscular junction (NMJ) transmission as a potential therapeutic target and biomarker have Clinical and electrophysiological correlates of muscle fatigability suggesting an element of NMJ dys- function have been described in patients with ALS over the past 50 years (4). Prior reports of decrement on repetitive nerve stimulation (RNS) corrected by neostigmine in poliomyelitis supported the hypothesis /doi.org/10.1172/jci.insight.97152 nsiaht.ici.ora on January 4. 2018, https:!/doi.ora/10,1172/ici.insiaht.97152Explanation / Answer
The study aimed to identify active compounds that could stabilize motor function and represent possible amyotrophic lateral sclerosis (ALD) therapeutics. ALS is a debilitating and fatal neurodegenerative disorder with no treatment available. Through a high-throughput screen of 3,850 small compounds in C. elegans harbouring a known TDP-43 mutation (conserved in humans), several compounds that rescued C. elegans motor dysfunction were identified. Further, these compounds were validated in zebrafish model harbouring TDP-43 mutation. Finally, ten active compounds were selected out of which pimozide was the most potent lead compound. The effects of pimozide were further explored in the C. elegans and zebrafish expressing other known ALS mutant genes including SOD1 and FUS, and in mice expressing SOD1 mutant. Pimozide was found to acutely restored neuromuscular transmission at the neuromuscular junction (NMJ) in all models tested. Pimozide was also found to act on a T-type calcium ion channels to boost the activity at the NMJ. Further, the impact of pimozide on 25 people with sporadic ALS was also over a 6-week period. Pimozide was found to be safe and tolerable at a 4 mg/day dose, and preliminary evidence of target engagement at the NMJ was also obtained.
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