Thursday July 28th 2016

Deciphering Lou Gehrig’s Disease

cientists are gradually unraveling mysteries surrounding Lou Gehrig’s disease, one of the least understood neurodegenerative conditions.

Using genetics and stem cells, separate teams of researchers are investigating amyotrophic lateral sclerosis, which is commonly known by the name of the famed baseball player whose career was cut short by the disease. The research into ALS is aimed at deciphering why motor neurons, the nerve cells in the brain and spinal cord that control movement, die off and how that process can be interrupted.

ALS has no cure. Currently, there is one drug on the market that appears to prolong modestly the lives of ALS sufferers, but more effective treatments are necessary, researchers say. Insight gleaned into ALS also could be helpful for understanding other diseases that affect neurons, such as Parkinson’s, Huntington’s and Alzheimer’s, they say.

ALS is a progressive, fatal disease in which motor neurons are destroyed and patients gradually lose the ability to move their bodies and even to breathe. The disease typically occurs in people between 40 and 60 years old and most patients die from respiratory problems within three to five years after their symptoms start, according to the National Institutes of Health.

Research into the condition has been limited, partly because the number of ALS patients is dwarfed by those of some other neurodegenerative diseases, like Alzheimer’s. Some 20,000 to 30,000 Americans are thought to be living with Lou Gehrig’s disease, and just 5,000 new cases are diagnosed each year, according to the NIH. ALS primarily strikes people who have no clear risk factors or family history of the disease; just 5% to 10% of cases are considered hereditary.

Scientists at Northwestern University and University of Chicago are studying the toxic buildup of proteins in ALS that result in the death of motor neurons. Preventing or removing these toxic buildups could be an effective way of treating the disease, they say. Proteins are made up of chains of amino acids that fold into different shapes. A protein with the wrong components, or that is misfolded, won’t work as it is supposed to.

In research published online last month by the journal Nature, Teepu Siddique, a professor of neurology at Northwestern University Feinberg School of Medicine, and his colleagues appear to have found a key protein that they say could be the answer to why the toxic proteins accumulate. The researchers identified a mutation, or a misfolding, in a protein called ubiquilin 2 that renders it ineffective. Normally, ubiquilin 2 clears out from neurons other proteins that aren’t working properly. The research team’s finding suggests that the ineffective ubiquilin 2 fails to remove toxic proteins from the system, allowing other proteins to accumulate.

Dr. Siddique says the research team looked at spinal cords of patients with ALS and the brains of people with ALS-related dementia and found that all had an accumulation of the mutated ubiquilin 2 protein, whereas people free of the disease didn’t. He says further research is needed to discover if there’s a way to return the mutated protein to its normal functioning, which could have implications for other conditions.

“If we are correct then correcting this pathway will not only take care of ALS but also other toxic proteins that build up, whether Alzheimer’s or Parkinson’s,” says Dr. Siddique.

Other researchers in the field say the finding is exciting, but further experiments are needed to show whether the misfolded ubiquilin 2 actually leads to a buildup of other toxic chemicals.

At the University of Chicago, Raymond Roos, a neurology professor and director of the ALS Clinic, is also studying how to clear misfolded proteins from the body. He and his colleagues have been investigating another “housekeeping” pathway known as the unfolded-protein response, or UPR, a chain of reactions that aims either to fix malfunctioning proteins or, if that fails, to kill them off.

The researchers are using mice with a key mutation associated with ALS on a gene called SOD-1. In mice that are deficient in the UPR process, the disease progresses at an accelerated pace, they found. Conversely, boosting the UPR process in mice with the mutant gene prolonged their life span. Though early, these data suggest that the UPR process could be a potential target for development of a treatment for ALS, Dr. Roos says.

In 1997, when film producer Jenifer Estess was diagnosed at age 35 with ALS, she asked her doctor why those dying motor neurons couldn’t be replaced with healthy ones. The doctor thought her question was ridiculous, recalls her sister, Valerie. “She was laughed out of the room,” she says.

The Estess sisters began reading research and found out about embryonic stem cells, which can grow into any type of cell in the body and are thought to be a potential way for the body to heal itself from many kinds of disease.

The Estesses, including a third sister, set up a private research foundation called Project A.L.S. in 1998, raising funds through Jenifer’s Hollywood contacts to sponsor stem-cell research. Jenifer died in 2003.

The nonprofit’s researchers and those of its collaborators, including Columbia University, Harvard University and Memorial Sloan-Kettering Cancer Center, have figured out how to use stem cells to create ALS motor neurons with the SOD-1 and other genetic mutations, says Hynek Wichterle, co-director of the Project A.L.S. research lab.

Researchers have been studying what chemical compounds help the ALS motor neurons stay healthy longer and which ones are toxic to them, he says. Several promising compounds have been identified and the group is in early-stage discussions with pharmaceutical companies to pursue further development, he says.

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