Study sheds light on why normal prion proteins may experience age-related mutations in inherited diseases

A new study sheds light on why normal prion proteins may experience age-related mutations in inherited diseases. Researchers at the Case Western Reserve University School of Medicine studied a previously discovered mutation in the prion protein in members of an extended family in Indiana who inherited the prion disease Gerstmann-Straussler-Sheinker (GSS).

GSS is a familial disease that causes movement disorders and has a course of approximately 3 years. This disease, and other prion diseases such as mad cow disease, are believed to be caused by the mutation of normally occurring proteins called prion proteins and are inevitably fatal.

In a laboratory study of the mutation that causes GSS in this family the mutant protein was found to assume its normal shape in the cell, but after it was unfolded it failed to return to its normal shape. This may explain why the disease is age-related since the healthy young cell can properly fold and maintain the mutant protein, but the deficits in the cellular machinery associated with aging might promote accumulation of the aberrant form of the prion protein resulting in disease.

There are several remaining questions, according to Robert Petersen, Ph.D., associate professor of pathology and neuroscience at Case and senior author of the study. "The most important question is," he said, "what is the exact nature of the improperly refolded form of the mutant protein. In addition, it will be important to address what features of the aging cell are most involved in defective protein folding, the understanding of which may result in novel therapeutic strategies for halting these devastating diseases."