In neurodegenerative diseases, clumps of insoluble proteins appear in patients' brains. These aggregates contain proteins that are unique to each disease, such as amyloid beta in Alzheimer's disease, but they are intertwined with small amounts of many other insoluble proteins that are normally present in a soluble form in healthy young individuals. For years, these other proteins were thought to be accidental inclusions in the aggregates, much as a sea turtle might be caught in a net of fish.
Now, in a surprising new finding, researchers at the University of California, San Francisco, report that many of the proteins present as minor components of disease aggregates actually clump together as a normal part of aging in healthy individuals.
The discovery, in the C. elegans roundworm, refutes a widespread belief that the presence of insoluble proteins is unique to degenerative disease and that the main proteins traditionally associated with each disease (like amyloid beta in Alzheimer's disease) are the only ones that could have an impact.
The research showed that a variety of common soluble proteins, such as those responsible for growth, can become insoluble and form aggregates in animals as they age. Moreover, the research demonstrated that gene manipulations that extend C. elegans lifespan prevent these common proteins from clumping.
The findings appear in the August 11, 2010 issue of the journal PLoS Biology and are freely available online at www.plosbiology.org.
"If you take people with Alzheimer's and look at their aggregates, there are many other proteins in the clump that no one has paid much attention to," said UCSF biochemist Cynthia Kenyon, PhD, director of the Larry L. Hillblom Center for the Biology of Aging at UCSF and senior author of the paper. "It turns out that about half of these proteins are aggregating proteins that become insoluble as a normal part of aging."
The team found that, in the presence of proteins specific to Huntington's disease, these other insoluble proteins actually sped up the course of the disease, indicating that they could be fundamental to its progression.
The findings indicate that widespread protein insolubility and aggregation is an inherent part of aging and that it may influence both lifespan and neurodegenerative disease, Kenyon said.
The presence of insoluble protein aggregates has long been recognized as a hallmark of such neurodegenerative diseases as Alzheimer's, Huntington's and amyotrophic lateral sclerosis (ALS). The team, led by first author Della C. David, PhD, a postdoctoral scholar in the UCSF Department of Biochemistry and Biophysics, asked a simple question that had never been addressed: Do normal proteins form insoluble clumps when normal, healthy individuals age?