Researchers find proteins that might restore damaged sound-detecting cells in the ear
Using genetic tools in mice, researchers at Johns Hopkins Medicine say they have identified a pair of proteins that precisely control when sound-detecting cells, known as hair cells, are born in the mammalian inner ear. The proteins, described in a report published June 12 in eLife, may hold a key to future therapies to restore hearing in people with irreversible deafness.
“Scientists in our field have long been looking for the molecular signals that trigger the formation of the hair cells that sense and transmit sound,” says Angelika Doetzlhofer, Ph.D.
, associate professor of neuroscience at the Johns Hopkins University School of Medicine.
“These hair cells are a major player in hearing loss, and knowing more about how they develop will help us figure out ways to replace hair cells that are damaged.”
In order for mammals to hear, sound vibrations travel through a hollow, snail shell-looking structure called the cochlea. Lining the inside of the cochlea are two types of sound-detecting cells, inner and outer hair cells, which convey sound information to the brain.
An estimated 90% of genetic hearing loss is caused by problems with hair cells or damage to the auditory nerves that connect the hair cells to the brain.
Deafness due to exposure to loud noises or certain viral infections arises from damage to hair cells. Un their counterparts in other mammals and birds, human hair cells cannot regenerate.
So, once hair cells are damaged, hearing loss is ly permanent.
Scientists have known that the first step in hair cell birth starts at the outermost part of the spiraled cochlea. Here, precursor cells start transforming into hair cells.
Then, sports fans performing “the wave” in a stadium, precursor cells along the spiral shape of the cochlea turn into hair cells along a wave of transformation that stops when it reaches the inner part of the cochlea.
Knowing where hair cells start their development, Doetzlhofer and her team went in search of molecular cues that were in the right place and at the right time along the cochlear spiral.
Of the proteins the researchers examined, the pattern of two proteins, Activin A and follistatin, stood out from the rest. Along the spiral path of the cochlea, levels of Activin A increased where precursor cells were turning into hair cells. Follistatin, however, appeared to have the opposite behavior of Activin A.
Its levels were low in the outermost part of the cochlea when precursor cells were first starting to transform into hair cells and high at the innermost part of the cochlea's spiral where precursor cells hadn't yet started their conversion.
Activin A seemed to move in a wave inward, while follistatin moved in a wave outward.
“In nature, we knew that Activin A and follistatin work in opposite ways to regulate cells,” says Doetzlhofer. “And so, it seems, our findings in the ear, the two proteins perform a balancing act on precursor cells to control the orderly formation of hair cells along the cochlear spiral.”
To figure out how exactly Activin A and follistatin coordinate hair cell development, the researchers studied the effects of each of the two proteins individually. First, they increased the levels of Activin A in the cochleas of normal mice.
In these animals, precursor cells transformed to hair cells too early, causing hair cells to appear prematurely all along the cochlear spiral.
In mice engineered to either overproduce follistatin or not produce Activin A at all, hair cells were late to form and appeared disorganized and scattered across multiple rows inside the cochlea.
“The action of Activin A and follistatin is so precisely timed during development that any disturbance can negatively affect the organization of the cochlea,” says Doetzlhofer. “It's building a house — if the foundation is not laid correctly, anything built upon it is affected.”
Looking more closely at why overproduction of follistatin results in disorganized hair cells, the researchers found that high levels of this protein caused precursor cells to divide more frequently, which in turn made more of them convert into inner hair cells in a haphazard way.
Doetzlhofer notes that her research in hair cell development, although fundamental, has potential applications to treat deafness caused by damaged hair cells: “We are interested in how hair cells evolved because it's an interesting biological question,” she says. “But we also want to use that knowledge to improve or develop new treatment strategies for hearing loss.”
The research was supported by the National Institute on Deafness and Other Communication Disorders (DC011571, DC013477, DC012972 and DC016538) and the David M. Rubenstein Fund for Hearing Research.
Materials provided by Johns Hopkins Medicine. Original written by Vandana Suresh, science writing intern for the Johns Hopkins Institute for Basic Biomedical Sciences. Note: Content may be edited for style and length.
Hearing Loss and Incident Dementia
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Hearing Loss Linked to Memory Loss, Dementia
Fortunately, there's a potential upside.
If this connection — shown in several recent and well-regarded studies — holds up, it raises the possibility that treating hearing loss more aggressively could help stave off cognitive decline and dementia.
Lin and other researchers have several theories about the possible explanation for the link between hearing and dementia, although they aren't yet sure which of them — if any — will prove true.
Lin is the author of several recent studies pointing to a link between hearing and cognitive problems ranging from mild impairment all the way to dementia.
In a 2013 study, he and his colleagues tracked the overall cognitive abilities (including concentration, memory and planning skills) of nearly 2,000 older adults whose average age was 77.
After six years, those who began the study with hearing loss severe enough to interfere with conversation were 24 percent more ly than those with normal hearing to see their cognitive abilities diminish.
Essentially, the researchers said, hearing loss seemed to speed up age-related cognitive decline.
In a 2011 study focusing on dementia, Lin and his colleagues monitored the cognitive health of 639 people who were mentally sharp when the study began.
The researchers tested the volunteers' mental abilities regularly, following most for about 12 years, and some for as long as 18 years.
The results were striking: The worse the initial hearing loss was, the more ly the person was to develop dementia. Compared with people of normal hearing, those with moderate hearing loss had triple the risk.
Lin is quick to point out that simply being at increased risk does not mean a person is certain to develop dementia.
“I have a 92-year-old grandmother who's had a moderately severe hearing loss for many years now,” Lin says. “She's sharp as a tack. I was talking to her about my research and she looks at me and says, 'Are you telling me I'm definitely going to get dementia?' “
“I said, 'Not by any means.' “
A recent study, led by Isabelle Mosnier of Assistance Publique-Hopitaux de Paris in France, offers more hope. Mosnier studied a group of 94 people ages 65 to 85 with profound deafness in at least one ear.
Each received a cochlear implant followed by twice-weekly auditory rehabilitation.
More than 80 percent of those with the lowest cognitive scores showed significant improvement one year after implantation, according to the study published March 12 in the journal JAMA Otolaryngology-Head & Neck Surgery.
P. Murali Doraiswamy, M.D., a professor of psychiatry and medicine at Duke University School of Medicine and coauthor of The Alzheimer's Action Plan, says that although the study had some shortcomings, “the improvement in cognition was huge — about double that seen with any of the current [U.
S. Food and Drug Administration] FDA drugs for treating Alzheimer's.” He adds that the findings about hearing loss affecting cognitive tests probably also apply to other senses such as vision, smell and touch. “Studies have shown that uncorrected vision problems raise the risk for dementia,” he says.
While the link between hearing loss and milder cognitive problems has been questioned by some, it is becoming increasingly accepted.
“Every doctor knows that hearing loss can result in cognitive problems, but they still don't focus on it as a priority when they evaluate someone with suspected dementia — which is a big missed opportunity,” Doraiswamy says.
“The benefits of correcting hearing loss on cognition are twice as large as the benefits from any cognitive-enhancing drugs now on the market. It should be the first thing we focus on.”
Still, he adds, “We need long-term controlled trials looking at whether cochlear implants can delay the onset of dementia in at-risk subjects, which will clinch the case.”