Inhibitors of SOD1 Interaction as an Approach to Slow the Progressive Spread of ALS Symptoms
Abstract
For most patients, the cause of amyotrophic lateral sclerosis (ALS) remains obscure. Researchers have known for more than 20 years that mutations in an enzyme called superoxide dismutase 1 (SOD1) can cause certain types of familial ALS. The Borchelt laboratory has been at the forefront of studies to understand how mutations in this protein cause disease. Over the course of close to 20 years of work, we have built a case that this SOD1 acquires some type of toxic property. Our data indicate that toxicity arises because the mutations change the configuration of the shape of the protein and that this altered shape changes this normally beneficial enzyme into a toxic protein. Our, and several others laboratories, have observed that mutant SOD1 in a "toxic" configuration can interact with normal SOD1 to transfer the toxic configuration to the normal protein. Moreover, another laboratory has recently demonstrated that the normal protein can transfer the toxic configuration to other normal proteins. These observations have prompted the hypothesis that spontaneous misfolding of normal SOD1 could induce a self-propagating process in which a toxic configuration is transferred between SOD1 proteins, and then between individual cells. This type of process can be called a "prion"-like mechanism. Scientists studying ALS, as well as those investigating other disorders like Parkinson s disease, are coming to realize that protein-misfolding can cause neurodegeneration to spread between neurons in the motor nervous system. From this line of thinking, it becomes possible to consider that sporadic ALS might be caused by a spontaneous change in the configuration of SOD1 -- whether by a spontaneous gene mutation of from exposure to free radicals -- and for this disordered configuration to spread. If this hypothesis is correct, then drugs that stabilize the normal structure of SOD1 could act to slow the progression of ALS, whether the disease is caused by a mutation or a spontaneous event. Our objective is to discover such drugs. It has been known since the SOD1 protein was first investigated more than 50 years ago that its normal state of being is for two SOD1 proteins to closely interact to form something we call a dimer (an enzyme composed to two copies of the SOD1 protein -- referred to as monomers). Almost 20 years ago Dr. Borchelt observed that SOD1 dimers can readily dissociate and re-associate in a process referred to as subunit exchange. This potentially important phenomenon has not been investigated as a potential mechanism for toxic conformations to spread between proteins. In this ALS drug-discovery effort, we have developed a novel approach that allows us to screen for drugs that would inhibit subunit exchange. The mechanism of action of such drugs may be to stabilize the normal dimeric interaction, or prevent re-association. In Aim 1, we will further develop and refine a high-throughput assay that measures SOD1 subunit exchange and use this new technology as a tool to discover drugs that inhibit the exchange process to stabilize the SOD1 dimer. Thus far, our data are encouraging, but very preliminary. Our idea sprung from our prior research and was also recently inspired anew by scientists that discovered the first drug -- called Tafamidis -- that effectively treats a different protein-misfolding disorder called familial amyloid polyneuropathy (FAP). In Aim 2, we will take a new approach to discover new combination-drugs for ALS based on drugs already approved by the Food and Drug Association (FDA) to treat other diseases. We will use a sophisticated approach to combine -- or pool -- mixtures of FDA-approved drugs in a special way that will allow us to detect combinations with unexpected activities in stabilizing SOD1 dimers. Other scientists have validated the method, but no one has ever tried it to discover drugs that can stabilize a PPI target like SOD1. By the end of the 2 years, we should have identifi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510218
Entities
People
- David Borchelt
Organizations
- United States Army
- University of Florida