Amyotrophic Lateral Sclerosis (ALS) is a progressive and long-lasting neurodegenerative disease that affects nerve cells in both the brain and spinal cord, notably targeting motoneurons. The disease was discovered by French neurologist Jean-Martin Charcot in 1869. There are two different types of ALS. “Sporadic” ALS can affect anyone, anywhere. This form represents 95% of the cases in the US. The other is “Familial” (FALS), linked with gene mutation that is transmitted and causes development of the disease with a probability of 50% in descendants.
The progressive degeneration of motor neurons in ALS ultimately leads to their complete demise. When motor neurons die, the brain’s ability to initiate and control muscle movement is lost. With voluntary muscle action affected progressively, people may lose the ability to speak, eat, move, and breathe.
Research over the past few decades has brought a wealth of new scientific understanding regarding the patho-physiology of this disease. Several treatment tracks have been determined by identifying potent targets.
In this article, Naomi Tsurabaya focused her studies on one such target, SOD1, for which mutations were identified in FALS patients.
By developing and characterizing a set of recombinant proteins, she set up a robust HTS assay (Z’ Factor > 0.75) to identify potent inhibitors of SOD1-Derlin-1 interaction. Hit triage and SAR studies delivered a set of interesting candidate compounds. Their potencies were confirmed in-vitro using either immunoprecipitation experiments or FP. Lastly, the most potent compounds were tested either on iPSC motoneurons taken from ALS patients, or on in-vivo ALS mouse models. Following incubation or treatment with these compounds, survival of ALS motoneurons was restored and increased.
The therapeutic choices to treat ALS are quite limited. Only two drugs are available, Edaravone and Riluzole, both of which reduce damage to motor neurons but also have many side effects.
Inhibiting SOD1-Derlin-1 interaction opens new possibilities for better treatment of ALS. It’s time to set up an assay to screen your compound libraries.
Naomi Tsuburaya et al.
Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
Nature Communications, 2018 Jul 10;9(1):2668
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder. Despite its severity, there are no effective treatments because of the complexity of its pathogenesis. As one of the underlying mechanisms of Cu, Zn superoxide dismutase (SOD1) gene mutation-induced ALS, SOD1 mutants (SOD1mut) commonly interact with an endoplasmic reticulum-resident membrane protein Derlin-1, triggering motoneuron death. However, the importance of SOD1-Derlin-1 interaction in in vitro human model and in vivo mouse model remains to be elucidated. Here, we identify small-molecular-weight compounds that inhibit the SOD1-Derlin-1 interaction by screening approximately 160,000 compounds. The inhibitor prevents 122 types of SOD1mut from interacting with Derlin-1, and significantly ameliorates the ALS pathology both in motoneurons derived from patient induced pluripotent stem cells and in model mice. Our data suggest that the SOD1-Derlin-1 interaction contributes to the pathogenesis of ALS and is a promising drug target for ALS treatment.