10:12pm Wednesday 08 April 2020

Discovery by Dartmouth researchers may improve understanding of neurodegenerative diseases

Henry Higgs, Ph.D.

The finding may lead to a better understanding of the development of neurodegenerative diseases, such as Huntington’s disease, Parkinson’s disease, and Alzheimer’s disease.

INF2 is known to be involved in the structure of the cytoskeleton—the network of filaments and proteins that gives the cell its shape—and, in particular, in the assembly of actin, a cytoskeletal protein that can be used by the cell to build whatever structures it needs.

“Before this discovery, no one thought the cytoskeleton played a role in mitochondrial division,” says Henry Higgs, Ph.D., a professor of biochemistry at Dartmouth’s Geisel School of Medicine.

For this study, he and Farida Korobova, a post-doctoral fellow in his lab, used a technique called RNA interference to lower the amount of INF2 that cells produced. In response, the cells’ mitochondria became larger and longer. The researchers then forced the cell to make an overactive version of INF2, and found that the mitochondria became shorter and smaller in these cells.

“We could actually see actin accumulate at sites where the mitochondria undergo fission,” Higgs says.

Other researchers had found that mutations in INF2 can cause Charcot-Marie-Tooth Disease (CMTD), a disorder that leads to peripheral neuropathy. Research has also showed that mitochondria undergo fission when they touch another cellular structure called the endoplasmic reticulum. These findings inspired Higgs and Korobova to examine the possible role of INF2 in mitochondrial dynamics.

“We were sort of stuck at first,” Higgs says. “We knew INF2 was on the endoplasmic reticulum and did a bunch of different things to actin. But we just could not find any cellular effects when we altered INF2. That’s because we were looking at the wrong organelle. When we looked at the mitochondria, the cellular effect became obvious.”

Mitochondria are involved not only in CMTD but in other neurodegenerative disorders as well. Changes in mitochondrial dynamics have been found to occur in Huntington’s disease, Parkinson’s disease, and Alzheimer’s disease. Neurons are extremely long cells and require energy all along their length. For a person to walk, for example, the mitochondria must be distributed correctly along the slender nerve cells that run all the way from the spinal cord down the leg. When the dynamics of how mitochondria join and split (fusion and fission) are altered, that may lead to disrupted distribution of mitochondria in the neuron, which in turn may lead to problems with the neuron’s functioning.

Scientists are not sure of the exact purpose of mitochondrial fusion and fission, but it is suspected that these processes help prevent excessive mutations from damaging the small mitochondrial genome. One theory holds that fission, besides being needed to make more mitochondria, shuttles off mutated copies of the genome into mitochondria that are then destroyed, keeping only mitochondria with clean copies of the genome. Fusion may allow a damaged mitochondria to be joined with a healthy one, “rescuing” the damaged mitochondria and sharing healthy components. Researchers are learning that mitochondrial fission and fusion play critical roles in maintaining functional mitochondria when the cell experiences environmental stresses.

Higgs and his colleagues hope that by understanding what exactly goes wrong in mitochondrial fission and fusion, they can learn more about the cellular basis of these neurodegenerative disorders. Learning that INF2 is another protein that is involved in mitochondrial fission, and that actin and the ER are also active players, is an important advance. The next step, Higgs says, is to investigate the details of this interplay more deeply.

“In the future, we’d like to look more closely at INF2 function in the nervous system, specifically in neurons, so that we can see how experimentally induced changes in INF2 affect neuronal function and mitochondrial distribution,” he says.

Read the full study.

The Geisel School of Medicine at Dartmouth, founded in 1797, strives to improve the lives of the communities it serves through excellence in learning, discovery, and healing. The nation’s fourth-oldest medical school, the Geisel School of Medicine has been home to many firsts in medical education, research, and practice, including the discovery of the mechanism for how light resets biological clocks, the first multispecialty intensive care unit, the first comprehensive examination of U.S. health care cost variations (The Dartmouth Atlas), and helping establish the first Center for Health Care Delivery Science, which launched in 2010. As one of America’s top medical schools, Dartmouth’s Geisel School of Medicine is committed to training new generations of diverse health care leaders who will help solve our most vexing challenges in health care.

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Contact: Derik Hertel, 603-650-1211 or [email protected]

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