“LIKE SEARCHING FOR MOBY DICK.” THAT’S HOW RICHARD MAYEUX, M.D., CO-DIRECTOR OF THE TAUB INSTITUTE FOR RESEARCH ON ALZHEIMER’S DISEASE AND THE AGING BRAIN AND DIRECTOR OF THE HUMAN GENETICS RESEARCH CORE, DESCRIBES THE QUEST FOR THE GENETIC CULPRITS IN ALZHEIMER’S DISEASE. “EVERYBODY’S BEEN LOOKING, AND WE’VE HAD LOTS OF SIGHTINGS, BUT NO ONE’S ACTUALLY IDENTIFIED ANYTHING AS THE KEY FACTOR IN ALZHEIMER’S DISEASE.”

In 1993, APOE, the only gene known to be associated with the late-onset form of Alzheimer’s disease, was discovered. But like such conditions as cancer and diabetes, Alzheimer’s is not a “single-gene” disease; many genes are likely to be involved. More recently, Dr. Mayeux and collaborators at other universities published work on one gene variant, SORL1, known to be involved in trafficking of proteins inside cells. The researchers screened 6,000 people from four ethnic groups, including the Dominican Republic population of Washington Heights, and found that those with variant forms of SORL1 produced less of that gene’s protein than usual, which may disrupt the traffic pattern and allow the amyloid precursor protein to be converted into toxic forms, contributing to the development of Alzheimer’s. “We believe SORL1 is an important piece of the Alzheimer’s gene puzzle,” Dr. Mayeux says.
     In another effort, Dr. Mayeux and his colleagues have formed a consortium of Alzheimer’s centers across the country to collaborate on a nationwide study involving the identification and genetic analysis of more than 1,000 families throughout the country where two or more first-degree relatives are living with Alzheimer’s disease. With Dr. Mayeux as the principal investigator, the first part of the study, which began in 2002, involved a genome-wide scan. The consortium has plans to submit another grant to the NIH for a large study of 1,000 Alzheimer’s disease cases and 1,000 healthy, matched controls, in which Columbia will lead the diagnostic aspect of the study as well as submit samples.
     Thanks to advanced brain imaging techniques, it’s been known for some time that Alzheimer’s disease begins in a small region of the brain within the hippocampus, the area where memories are formed, called the entorhinal cortex. Columbia researchers Scott Small, M.D., and Tae-Wan Kim, Ph.D., have used that information to identify a key group of proteins that have to do with transporting molecules within the brain, including the amyloid precursor protein, which if not transported correctly begins to misfold, become insoluble, and then aggregate and evolve into plaques.
     “What they did was very clever. Instead of the usual strategy, taking samples from the brains of people with Alzheimer’s and samples from normal controls, they first used functional imaging to obtain high-resolution views of the hippocampus and guide them to the entorhinal cortex, to make sure that what they were looking at was a change specific to that region,” says Dr. Mayeux.
     Drs. Small and Kim then used DNA microarrays to study differences in gene expression in brain tissue from normal adults and adults with Alzheimer’s disease, specifically in the entorhinal cortex. They found four candidate genes that were overexpressed in the entorhinal cortex in people with Alzheimer’s disease. One of the genes, VPS35, appears to be the best correlated with Alzheimer’s and is now being studied. “That’s started a lot of excitement,” says Dr. Mayeux. “It’s a subtle disturbance, but one that’s important and potentially modifiable.”
     Alzheimer’s disease devastates the lives of the elderly, while another genetically linked neurological condition, spinal muscular atrophy, takes its toll on the very young. SMA, a disorder in which the nerve cells of the spinal cord waste away, is the No. 1 genetic killer of children under the age of 2. It affects one in every 6,000 children and is caused by the mutation of a single gene – SMN1, or survival motor neuron 1. The NIH has identified SMA as the neurological disease with the greatest potential for treatment or cure in the near future, and Columbia may well be where that discovery happens. Our new Motor Neuron Center, opened in November 2005, brings together some of the world’s top experts in SMA and amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease, another disease of the motor neurons). More than 40 leading researchers from numerous disciplines, including neurobiology, neurology, genetics, pathology, cell biology, physiology, anatomy, chemistry, and pediatrics, have converged in this translational research program aimed at answering key questions about motor neurons: Why and how do they die in ALS and SMA? How do precursor cells develop into healthy motor neurons, and what keeps them alive?
     One of the leading researchers involved in the Center, Umrao Monani, Ph.D., assistant professor of neurology, has studied SMA for more than a decade. His research has focused on creating a genetic mouse model of the disease – not an easy task, because SMA is a uniquely human disease not found in mice – and using that model to try to find targets for SMA treatment. “From these studies, we’ve learned that there may be a window of time during which high levels of the protein generated by the SMN gene – the SMN protein – are required for normal motor neuron development, and after you’ve passed through that window, the levels don’t need to be so high,” says Dr. Monani. “Is that time during fetal development or after birth? We don’t know, although there’s some suggestion that in humans the time is postnatal.” Since all people have an SMN2 gene – a nearly identical backup copy of SMN1 – scientists may be able to boost the activity of that gene to produce enough of the needed protein during that critical window of motor neuron development, possibly neutralizing the disease.
     One of the leading mysteries of motor neurons – in health and disease – has been solved by Columbia scientist Thomas Jessell, Ph.D., the Claire Tow Professor of Biochemistry and Molecular Biophysics and another member of the Motor Neuron Center. He and several colleagues have unlocked a critical part of the regulatory code that tells motor neurons how to connect to specific muscles in the limbs. The code involves 21 members of a family of genes known as Hox – genes that had long been known to play a part in brain development but had not been studied much for their role in the spinal cord. Dr. Jessell reported his findings in the journal Cell.
     Understanding how Hox proteins regulate the formation of the complex wiring system that the spinal cord uses to control our muscles is essential to restoring function that has been stolen by neurodegenerative diseases like SMA or ALS, as well as by spinal cord injuries. “If cell replacement therapies are to work in the future, it may not be enough to make new motor neurons,” says Dr. Jessell. “We will have to understand how to connect the neurons to the right muscles in order to restore movement. The more we understand the basic workings of the entire locomotor circuit, the better chance there is of developing regenerative strategies to restore movement.” The Motor Neuron Center is part of Columbia’s large and growing Center for Neuroscience Initiatives, which is developing and implementing new programs and centers that will accelerate the translation of fundamental discoveries of neuroscience research into new therapies for neurological and psychiatric disorders.
     This research will take a giant leap forward with the creation of the new Jerome L. Greene Science Center, soon to be the home for Columbia’s growing initiative in Mind, Brain, and Behavior. To be built with a $200 million gift from Dawn M. Greene and the Jerome L. Greene Foundation – the largest bequest ever received by Columbia and the largest private gift received by any U.S. university for the creation of a single facility – the Greene Center will bring together scientists from multiple disciplines to explore the relationship among gene function, brain wiring, and behavior to probe the root causes of such neurodegenerative diseases as Parkinson’s, Alzheimer’s, and ALS and such psychiatric and neurodevelopmental disorders as schizophrenia and autism.
     Columbia neuroscientists are already exploring the use of genetically encoded probes and sensors to monitor the activity of neural circuits deep within the brain. “For example, the ability to use genetics to express genes in neurons that are vulnerable in diseases like Alzheimer’s and Parkinson’s offers us a way of understanding the nature of the injury to those neurons. Is it applied solely to the neuron that dies, or is it part of a much larger circuit defect?” asks Dr. Jessell, who will lead the Greene Center with Nobel laureates Richard Axel, M.D., University Professor, and Eric Kandel, M.D., University Professor. “And in conditions like autism and neurodevelopmental disorders, we can use modern genetic experimental methods to map out the circuitry in a normal brain and then begin to examine with increasingly fine resolution what’s gone wrong with those circuits in the brains of people with disorders like autism. It’s an exciting challenge, bringing psychiatry together with basic neuroscience, and it’s almost certain that these advances in experimental genetics will begin to have an impact on how we treat these neurodevelopmental disorders.”

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