One of the common features of neurodegenerative diseases such as ALS, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease is the presence of proteins that are misfolded. Evidence for the misfolded proteins is found in the brain and spinal cord and much research has focused on the adverse consequences of these misfolded proteins for the brain and spinal cord. On the other hand, tissues outside of the nervous system appear mostly unaffected by these same proteins, which are clearly present at similar levels.
Drs. Miller and Weihl are focused on figuring out how the liver handles misfolded SOD1 protein to prevent damage. Misfolded SOD1 causes inherited amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s Disease), a disease characterized by progressive weakness, muscle atrophy, loss of ability to speak and swallow, and death from failure of respiratory muscles 3-5 years after the beginning of the disease. Miller and Weihl hypothesize that a substance found in the liver acts to modify SOD1 misfolding and thus ameliorate its toxic effects.
In this project, they will isolate and identify one or more specific liver proteins that inhibit protein folding in these cells. If these factors can be introduced into the brain and spinal cord, it may prevent toxicity of SOD1 in both familial and sporadic ALS, and may even lead to novel therapeutic approaches for other neurodegenerative diseases involving protein misfolding.
“Identifying liver proteins that decrease mutant SOD1 misfolding and decrease SOD1”
NIH-NINDS, R21NS072584-02 (Miller, PI)
The goal of this study is to identify the protein or proteins in the liver that lead to normal handling of SOD1 protein despite the mutations.
Updated October 2012