Research seeks to better understanding the links between protein aggregation and neurodegenerative disease

THE PROBLEM

Researchers in Dr. Shewmaker’s Lab are studying proteins that inappropriately aggregate in the neurons of patients with amyotrophic lateral sclerosis (ALS), a fatal disease that specifically affects the neurons that control movement. For unknown reasons, ALS affects military veterans twice as frequently as the general population, regardless of branch or specialty. There are no drugs that reverse or stop ALS disease progression, so there is an imperative to identify new therapeutic targets.

 

The pathological aggregation of certain proteins is not unique to ALS. Many similar neurodegenerative diseases share this phenomenon, albeit different disease may be linked to different proteins. The Shewmaker Lab is focused on understanding this general phenomenon. Elucidating why and how certain proteins pathologically aggregate may help develop future therapeutic interventions against numerous diseases, including Alzheimer’s and Parkinson’s diseases.

WHAT WE'RE DOING

The millions of proteins within cells undergo numerous modifications as part of their normal functions. The Shewmaker Lab is determining how these modifications alter the way certain proteins aggregate (either functionally or pathologically). Understanding these modifications will enable development of new pharmacological treatments.

Our Findings

Mutations in the protein known as FUS cause subtypes of ALS. The Shewmaker lab discovered extensive modifications of FUS following conditions that cause stress to cells.

 

The Shewmaker lab and collaborators discovered that certain modifications of FUS, which are performed by enzymes known as kinases, can reduce FUS’s potential to aberrantly aggregate and cause cell toxicity.

 

Researchers in the Shewmaker Lab have developed high-throughput assays in yeast cells that can quickly assess how mutations alter the aggregation and toxicity of proteins that cause neurodegeneration. These methods enable fast and inexpensive experimentation that can aid in drug discovery.