Brain Chemistry

The identity of the major protein in tanglelike inclusions associated with both amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, and a common family of brain-wasting disorders known as frontotemporal lobar dementia (FTD) has been revealed (Science 2006, 314, 130).

In recent years, researchers have been finding protein-based tangles and plaques in tissue associated with many neurodegenerative diseases, including Alzheimer's and Parkinson's. Identifying the proteins in these cellular inclusions has, in some cases, opened pathways toward therapeutic targets.

There are no treatments for ALS or FTD, says research leader Virginia M. Y. Lee of the University of Pennsylvania School of Medicine. "To have this molecular identity is incredibly important" for understanding and perhaps treating these conditions, comments neurodegenerative disease researcher Michael Hutton of the Mayo Clinic Jacksonville, in Florida.

Lee's team used biochemical and antibody-based methods to isolate, characterize, and identify TDP-43 as the protein in inclusions of diseased brain tissue. In affected tissue, the protein, which is normally present in nuclei, accumulates abnormally in the cells' cytoplasm, extensions known as neurites, and, in some cases, nuclei.

"We believe these TDP-43 tangles will turn out to have a causal role" in ALS and FTD, Lee says, noting that finding this molecular connection among the disorders came as a surprise. "We went after the disease protein in FTD, and then we found it was also in ALS," she says. Now she plans to investigate TDP-43's normal cellular roles and determine if the TDP-43 tangles are indeed central to the pathology of these diseases.