Research by biochemistry professor Henry Higgs and his research team has led to new breakthroughs into the cause of the kidney disease Focal and segmental glomerulosclerosis and the neurodegenerative disease Charcot-Marie-Tooth disease.
Higgs's lab discovered over a year ago that the INF2 protein plays a key role in the fission process of mitochondria, which led to a recent collaborative publication with researchers at Harvard Medical School about how mutations on the INF2 protein are related to the formation of the FSGS kidney disease.
The disease hinders the kidney's ability to function, requiring patients to undergo a full kidney transplant.
"This was part of the desert of the genome that did not have any mapped function yet," said Higgs. "We started doing research on this protein with absolutely no idea what it did."
Higgs' lab focused its attention on the formin family of proteins, which includes the INF2 protein.
They discovered that the protein, which is generally found in the cell's endoplasmic reticulum, helps in the fission process of mitochondria.
This function of the INF2 protein was previously unknown, Higgs said.
Vinay Ramabhadran GR'12, who began working with Higgs in his lab in 2006, said that their research aimed to discover the most fundamental source of the disease.
"The key is to start off small at the protein level, then go to the cellular level, then organs and then the whole body," he said.
Mitochondria fission and fusion is important because it protects the mitochondria's genome. Higgs hypothesized that fission is used to separate out the damaged parts of the genome.
In their research, Higgs and his research assistants found that when the INF2 protein mutates incorrectly, a cell's mitochondria can no longer perform fission normally, and the cell becomes diseased, Higgs said.
"People have been looking at how mitochondria have been undergoing fission for a while, but there was a missing step that nobody knew how it worked. This filled that step," Higgs said.
After Higgs and his team published an initial paper on the INF2 protein, his lab was contacted by a group from Harvard Medical School led by Martin Pollak that was researching mitochondrial fission and its connection to the FSGS kidney disease.
The two labs then worked together to produce a paper connecting the INF2 protein to problems with mitochondrial fission in the FSGS disease, Higgs said.
Shortly after, a French lab led by Corinne Antignac and Geraldine Mollet published a paper connecting mutations on the INF2 protein to the neurodegenerative Charcot-Marie-Tooth disease.
The disease, currently incurable, affects 1 in 2,500 people and causes loss of muscle tissue and touch sensation in various parts of the body, according to Higgs.
The long-term goal of research related to the INF2 protein is to develop drugs to prevent the INF2 mutation that causes neurodegenerative diseases, according to Farida Korobova, who works on Higgs' research team.
Higgs and his research team hope that their research will help with future discoveries about common neurodegenerative diseases like Alzheimer's, Parkinson's and Huntington's diseases, Korobova said.
"It is not that direct, and it is a long way from a cure, but it is a starting direction," Korobova said.
In the more immediate future, Higgs and his research team said they hope that their research can be used to help identify characteristics of individuals susceptible to developing these neurodegenerative diseases, according to Higgs. Identifying these diseases early in their development can improve patients' outcomes and slow the progress of the diseases.
There is much more research to be done about the INF2 protein and its effect on mitchondrial fission, Higgs said.
"We strongly suspect now that our mechanism in Science journal is incomplete and we are trying to add to that mechanism," Higgs said.
