Discovery of extremely long-lived proteins may provide insight into cell aging and neurodegenerative diseases
One of the big mysteries in biology is why cells age, but a team led by Martin Hetzer has recently provided some intriguing clues. He and his group have discovered a weakness in a component of nerve cells that may explain how the aging process occurs in the brain. They found that certain proteins, called extremely long-lived proteins (ELLPs), which are found on the surface of the nucleus of neurons, have a remarkably long lifespan. Whereas the lifespan of most proteins totals two days or less, the scientists identified ELLPs in the rat brain that were as old as the organism, a finding they reported in Science. Their results suggest the proteins last an entire lifetime.
ELLPs make up the transport channels on the surface of the nucleus, called nuclear pore complexes, which function as gates controlling what materials enter and exit. Unlike other proteins in the body, ELLPs are not replaced when they sustain aberrant chemical modifications and other damage. Damage to the ELLPs weakens the ability of the nuclear pore complexes to safeguard the cell's nucleus from toxins. The toxins may alter the cell's DNA and the activity of genes, resulting in cellular aging.
"The fundamental defining feature of aging is an overall decline in the functional capacity of various organs such as the heart and the brain," Hetzer says. "This decline results from deterioration of the homeostasis, or internal stability, within the constituent cells of those organs. Recent research in several laboratories has linked breakdown of protein homeostasis to declining cell function."
The results that Hetzer and his team report suggest that declining neuron function may originate in ELLPs that deteriorate as a result of damage over time.
"All cells combat functional deterioration of their protein components through the process of protein turnover, in which the potentially impaired parts of the proteins are replaced with new functional copies," he explains. "Our results also suggest that a class of proteins exists that cannot be replaced. Therefore, these proteins might be part of a general aging mechanism leading to age-related defects in nuclear function."
The findings may prove relevant to understanding the molecular origins of aging and such neurodegenerative disorders as Alzheimer's and Parkinson's diseases.