Many of the proteins present as minor components of Alzheimer's and other neurodegenerative diseases actually clump together as a normal part of aging in healthy individuals, researchers at the University of California, San Francisco, have found.
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.
In addition, the research demonstrated that gene manipulations that extend C. elegans lifespan prevent these common proteins from clumping.
"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. It turns out that about half of these proteins are aggregating proteins that become insoluble as a normal part of aging," said UCSF biochemist Dr. Cynthia Kenyon, director of the Larry L. Hillblom Center for the Biology of Aging at UCSF and senior author of the paper.
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, said Kenyon.
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 Dr. Della C. David, 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?
They identified roughly 700 proteins in a C. elegans worm that become insoluble as the animal ages.
These insoluble proteins are highly over-represented in the aggregates found in human neurodegeneration, the researchers wrote in their paper.
They found that many of the proteins that became insoluble were already known to accelerate the aging process and to influence the aggregation of the major disease proteins.
Yet even in the healthy aging worms, these proteins had a propensity for clumping and forming hard, rocklike structures.
The team found that this aggregation was significantly delayed or even halted by reducing insulin and IGF-1 hormone activity, whose reduction is known to extend animal lifespan and to delay the progression of Huntington's and Alzheimer's disease in animal models of neurodegenerative diseases.
While there are indisputable differences between worms and men, the roundworm C. elegans (Caenorhabditis elegans) often has led the way in advancing our understanding of human biology, notably in such areas as the mechanism of cell death, insulin pathways, the genes involved in cancer, and aging.
Some of those advances have originated in Kenyon's lab, including the discovery that blocking the activity of a single gene in C. elegans doubled the animal's lifespan. The gene, known as daf-2, encodes a receptor for insulin as well as for IGF-1. The same or related hormone pathways have since been shown to affect lifespan in fruit flies and mice, and are thought to influence lifespan in humans.
The findings appear in the latest issue of the journal PLoS Biology.