Tryptophan 32 mediates SOD1 toxicity in a in vivo motor neuron model of ALS and is a promising target for small molecule therapeutics.

Tryptophan 32 mediates SOD1 toxicity in a in vivo motor neuron model of ALS and is a promising target for small molecule therapeutics. Neurobiol Dis. 2018 Dec 04;: Authors: DuVal MG, Hinge VK, Snyder N, Kanyo R, Bratvold J, Pokrishevsky E, Cashman NR, Blinov N, Kovalenko A, Ted Allison W Abstract SOD1 misfolding, toxic gain of function, and spread are proposed as a pathological basis of amyotrophic lateral sclerosis (ALS), but the nature of SOD1 toxicity has been difficult to elucidate. Uniquely in SOD1 proteins from humans and other primates, and rarely in other species, a tryptophan residue at position 32 (W32) is predicted to be solvent exposed and to participate in SOD1 misfolding. We hypothesized that W32 is influential in SOD1 acquiring toxicity, as it is known to be important in template-directed misfolding. We tested if W32 contributes to SOD1 cytotoxicity and if it is an appropriate drug target to ameliorate ALS-like neuromuscular deficits in a zebrafish model of motor neuron axon morphology and function (swimming). Embryos injected with human SOD1 variant with W32 substituted for a serine (SOD1W32S) had reduced motor neuron axonopathy and motor deficits compared to those injected with wildtype or disease-associated SOD1. A library of FDA-approved small molecules was ranked with virtual screening based on predicted binding to W32, and subsequently filtered for analogues using a pharmacophore model based on molecular features...
Source: Neurobiology of Disease - Category: Neurology Authors: Tags: Neurobiol Dis Source Type: research