GROUNDBREAKING SCIENCE
Protein Folding Gone Awry

UT's Ron Wetzel seeks to develop molecules that can block the formation of amyloid fibrils common to several deadly diseases.

Many unknowns surround the diseases typified by deposits of amyloid fibrils inside body tissue. But, to UT Professor of Medicine Ron Wetzel, nothing is more mysterious than how the process starts.

This left-handed parallel beta helix folding motif is one possible model for the fundamental amyloid fibril fold.

Alzheimer's, Lou Gehrig's, Parkinson's, Huntington's, and prion diseases such as Creutzfield-Jacob Disease-the diseases are many and the proteins forming the amyloid fibrils differ. However, the fibrils are alike because all are composed of similarly misfolded proteins. Nearly insoluble in water, the fibrils tend to aggregate and make deposits, complicating efforts to manage their associated diseases."Understanding how fibrils form and grow by bringing more molecules into the structure could help us design inhibitors to block the process," Wetzel said. His group focuses on Alzheimer's and Huntington's diseases.

Each disease has its own protein that runs into trouble during normal folding. "The protein goes down an alternative folding pathway," he says. "Once started, the process is often self-sustaining."

According to Wetzel, some conditions may result from the deposition of masses of fibrils that can interfere with tissue structure. But other diseases may involve relatively small numbers of fibrils that may directly kill specific types of cells.

Using electron microscopes, Wetzel's group has found that amyloid fibrils from any protein resemble short, relatively rigid, twisted ropes. Higher-resolution methods, such as X-ray crystallography and nuclear magnetic resonance, fail to resolve fibril structure for various technical reasons.

To overcome this barrier to understanding how different proteins evolve to form different shapes and how they get tangled up to form highly stable amyloid structures, Wetzel's lab fell back on classical methods of piecing together misfolded proteins. They have excelled at growing in the test tube amyloid fibrils and aggregates associated with Alzheimer's and Huntington's diseases.

Wetzel seeks to understand how molecular "chaperones" designed to eliminate protein misfits can interfere with amyloid formation in Huntington's disease. "This knowledge," says Wetzel, "could help us figure out how to make the disease process stop."

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