Can a heart disease lab advance our understanding of neurodegeneration? It can, it turns out, at least when it comes to the search for common underlying mechanisms. Published in this week’s PNAS online, research on a type of heart failure linked to misfolded protein aggregates taps right into the shifting debate about whether visible protein aggregates or elusive protein oligomers are to blame for amyloid diseases.
Atsushi Sanbe and colleagues in Jeffrey Robbins' Howard Hughes lab at Cincinnati Children’s Hospital Medical Center collaborated with Rakez Kayed and Charlie Glabe at the University of California, Irvine. They report that they can reverse even late-stage heart failure in an inducible on-off mouse model by reducing levels of the offending amyloidogenic protein even while existing, overt deposits remain in place. “Mouse viability was invariably linked to decreased amyloid oligomer levels, with little or no decrease in the aggresomes,” the authors write.
The study ties into AD research at several levels. First, it echoes findings reported this summer by Karen Ashe’s group at the University of Minnesota Medical School in Minneapolis. Using a similar transgenic approach to explore how tau relates to pathogenesis, these scientists found that shutting off further tau expression after tau pathology and neurodegeneration were already in full swing did not reduce tangles but did improve memory function in the mice (SantaCruz et al., 2005). Similarly, the mice in the present study, expressing a mutant protein known to cause a human form of cardiomyopathy, recovered cardiac function and survived longer when the mutant protein was turned off during the course of disease. Both studies suggest that future therapies quenching production of oligomeric protein species might do some good even when the disease is already established.
Second, the present study supports recent work by Steven Finkbeiner’s group at the University of California, San Francisco. These investigators showed that intracellular inclusions of mutant huntingtin arise as the neuron tries to sequester the protein and that the inclusions protect affected neurons from dying (Arrasate et al., 2004). More broadly, the Cincinnati investigators add a voice to a growing chorus of researchers who consider deposits to be less toxic than smaller versions of the respective disease proteins across a range of neurodegenerative and other amyloidogenic diseases.
The present line of investigation in the Jeffrey lab grew out of a collaboration with Glabe after the Californian researchers first described their production of an antibody that appeared to recognize small oligomeric forms not only of Aβ but also of proteins involved in a range of amyloidogenic diseases (Kayed et al., 2003). That finding was greeted by surprise and some skepticism. The Glabe lab sent its unusual antibody out to numerous labs for confirmation and extended studies (now BioSource International sells it), and results from some of those labs are beginning to appear in the literature.
Kayed and Glabe’s work raised questions about whether amyloid oligomers of different proteins share a common structure, and just how broadly such oligomers may act in protein deposition diseases. The Robbins lab explored the example of desmin-related cardiomyopathy (DRM), a disease in which amyloid aggregates form around the nucleus of heart muscle cells. This human disease is caused by a missense mutation in αB-Crystallin, the most abundant small heat shock chaperone in the heart. Beyond this condition, the Cincinnati researchers found amyloid in heart muscle cells from other forms of human cardiomyopathy. In summary, they propose that amyloid oligomers forming inside the sarcoplasm of heart muscle cells might be a prevalent contributor to cardiac disease (Sanbe et al., 2004).—Gabrielle Strobel
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