Genetic Mutation Linked with Typical Form of Migraine

A research team led by a Howard Hughes Medical Institute investigator at the University of California, San Francisco has identified a genetic mutation that is strongly associated with a typical form of migraine.

In a paper published on May 1 in Science Translational Medicine, the team linked the mutation with evidence of migraine in humans, in a mouse model of migraine and in cell culture in the laboratory.

The mutation is in the gene known as casein kinase I delta (CKIdelta).

“This is the first gene in which mutations have been shown to cause a very typical form of migraine,” said senior investigator Louis J. Ptáček, an investigator at HHMI and a professor of neurology at UCSF. “It’s our initial glimpse into a black box that we don’t yet understand.”

Migraine, the causes of which are still unknown, affects 10 to 20 percent of all people, and causes “huge losses in productivity, not to mention immense suffering,” said Ptáček. Typical symptoms include a pounding headache; lowered pain threshold; hypersensitivity to mild stimuli including sound and touch; and aura, which Ptáček describes as “a visual sensation that presages the headache to come.”

The paper presents both clinical and basic scientific evidence that the mutation causes migraine.

In the study, the scientists first analyzed the genetics of two families in which migraine was common, and found that a significant proportion of migraine sufferers in the families either had the mutation or were the offspring of a mutation carrier.

In the laboratory, the team demonstrated that the mutation affects the production of the casein kinase I delta enzyme, which carries out a number of vital functions in the brain and body. “This tells us that the mutation has real biochemical consequences,” said Ptáček.

The scientists then investigated the effects of the mutation in a line of mice that carry it. “Obviously, we can’t measure headache in a mouse,” Ptáček noted, “but there are other things that go along with migraine that we can measure.”

Pain threshold, explained Ptáček, can be lowered in mice by the administration of nitroglycerin. The mutant mice had a significantly lower threshold for nitroglycerin-induced peripheral pain than did normal mice.

Another piece of evidence was cortical spreading depression (CSD), a wave of electrical “silence” in the brain that follows electrical stimulation, spreading out from the point of stimulation in a predictable pattern. The researchers found that the mutant mice had a significantly lower electrical threshold for the induction of CSD.

The CSD experiments are “especially intriguing,” said Ptáček, because it is known that CSD spreads through the brain at 3 millimeters per minute. “Functional brain imaging has shown that in the occipital lobes of people with migraine aura, changes in blood flow spread at the same rate.”

Finally, Ptáček and his team found that astrocytes – brain cells that are essential to neuronal functioning and health – from the brains of mutant mice showed increased calcium signaling compared with astrocytes from the brains of normal mice.

“This is significant because we think astrocyte functioning is very, very relevant to migraine,” said Ptáček. “This is an enzyme, and so it modifies proteins. The question is, which protein or proteins does it modify that is relevant to migraine? How does it change astrocyte activity?”

The research “puts us one step closer to understanding the molecular pathway to pain in migraine,” he said. “And, as we come to a clearer understanding, we can start thinking about better therapies. Certain molecules might be targets for new drugs.” There are good drugs now, said Ptáček, “but they only help some patients, some of the time. The need for better treatments is huge.”

The CKIdelta mutation is “far from the only mutation likely to be associated with migraine,” Ptáček cautioned. “There are likely several, in different combinations in different people. This is simply the first one we’ve found.”

Discovering ‘Needle in a Haystack’ For Muscular Dystrophy Patients

Muscular dystrophy is caused by the largest human gene, a complex chemical leviathan that has confounded scientists for decades. Research conducted at the University of Missouri and described this month in the Proceedings of the National Academy of Sciences has identified significant sections of the gene that could provide hope to young patients and families.

MU scientists Dongsheng Duan, PhD, and Yi Lai, PhD, identified a sequence in the dystrophin gene that is essential for helping muscle tissues function, a breakthrough discovery that could lead to treatments for the deadly hereditary disease. The MU researchers “found the proverbial needle in a haystack,” according to Scott Harper, PhD, a muscular dystrophy expert at The Ohio State University who is not involved in the study.

Duchenne muscular dystrophy (DMD), predominantly affecting males, is the most common type of muscular dystrophy. Children with DMD face a future of rapidly weakening muscles, which usually leads to death by respiratory or cardiac failure before their 30th birthday.

Patients with DMD have a gene mutation that disrupts the production of dystrophin, a protein essential for muscle cell survival and function. Absence of dystrophin starts a chain reaction that eventually leads to muscle cell degeneration and death. While dystrophin is vital for muscle development, the protein also needs several “helpers” to maintain the muscle tissue. One of these “helper” molecular compounds is nNOS, which produces nitric oxide that can keep muscle cells healthy during exercise.

"Dystrophin not only helps build muscle cells, it’s also a key factor to attracting nNOS to the muscle cell membrane, which is important during exercise," Lai said. "Prior to this discovery, we didn’t know how dystrophin made nNOS bind to the cell membrane. What we found was that dystrophin has a special ‘claw’ that is used to grab nNOS and bring it to the muscle cell membrane. Now that we have that key, we hope to begin the process of developing a therapy for patients."

Stem Cell Research Helps to Identify Origins of Schizophrenia

New University at Buffalo research demonstrates how defects in an important neurological pathway in early development may be responsible for the onset of schizophrenia later in life.

The UB findings, published in Schizophrenia Research, test the hypothesis in a new mouse model of schizophrenia that demonstrates how gestational brain changes cause behavioral problems later in life – just like the human disease.

Partial funding for the research came from New York Stem Cell Science (NYSTEM).

The genomic pathway, called the Integrative Nuclear FGFR 1 Signaling (INFS), is a central intersection point for multiple pathways of as many as 160 different genes believed to be involved in the disorder. 

“We believe this is the first model that explains schizophrenia from genes to development to brain structure and finally to behavior,” says lead author Michal Stachowiak, PhD, professor in the Department of Pathology and Anatomical Sciences in the UB School of Medicine and Biomedical Sciences. He also is director of the Stem Cell Engraftment & In Vivo Analysis Facility at the Western New York Stem Cell Culture and Analysis Center at UB.

A key challenge with the disease is that patients with schizophrenia exhibit mutations in different genes, he says.

“How is it possible to have 100 patients with schizophrenia and each one has a different genetic mutation that causes the disorder?” asks Stachowiak. “It’s possible because INFS integrates diverse neurological signals that control the development of embryonic stem cell and neural progenitor cells, and links pathways involving schizophrenia-linked genes.

“INFS functions like the conductor of an orchestra,” explains Stachowiak. “It doesn’t matter which musician is playing the wrong note, it brings down the conductor and the whole orchestra. With INFS, we propose that when there is an alteration or mutation in a single schizophrenia-linked gene, the INFS system that controls development of the whole brain becomes untuned. That’s how schizophrenia develops.”

Using embryonic stem cells, Stachowiak and colleagues at UB and other institutions found that some of the genes implicated in schizophrenia bind the FGFR1 (fibroblast growth factor receptor) protein, which in turn, has a cascading effect on the entire INFS.

Berkeley Lab Scientists Help Develop Promising Therapy for Huntington’s Disease

There’s new hope in the fight against Huntington’s disease. A group of researchers that includes scientists from the U.S. Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab) have designed a compound that suppresses symptoms of the devastating disease in mice.

The compound is a synthetic antioxidant that targets mitochondria, an organelle within cells that serves as a cell’s power plant. Oxidative damage to mitochondria is implicated in many neurodegenerative diseases including Alzheimer’s, Parkinson’s, and Huntington’s.

The scientists administered the synthetic antioxidant, called XJB-5-131, to mice that have a genetic mutation that triggers Huntington’s disease. The compound improved mitochondrial function and enhanced the survival of neurons. It also inhibited weight loss and stopped the decline of motor skills, among other benefits. In short, the Huntington’s mice looked and behaved like normal mice.

Based on their findings, the scientists believe that XJB-5-131 is a promising therapeutic compound that deserves further investigation as a way to fight neurodegenerative diseases.

They report their research in a paper that appears online Nov. 1 in the journal Cell Reports.