SfN Members Win 2022 Kavli Prize in Neuroscience
SfN members Harry T. Orr and Huda Y. Zoghbi, alongside fellow neuroscientists Jean-Louis Mandel and Christopher A. Walsh, have been awarded the 2022 Kavli Prize in Neuroscience for pioneering the discovery of genes underlying a range of brain disorders. The laureates will share $1 million.
“These scientists discovered the genetic basis of multiple brain disorders, and elucidated the pathways by which these genes work,” says Chair of the Neuroscience Committee, Kristine B. Walhovd in a press release.
Before scientists mapped the human genome in the early 2000s, the quest for genes was a laborious process. Four persistent neuroscientists are recognized for pioneering the discovery of genes underlying a range of serious brain disorders and establishing a blueprint for neuroscience research, diagnosis and treatment for Fragile X syndrome, spinocerebeller ataxia, Rett syndrome, and rare forms of epilepsy and autism spectrum disorder.
Harry T. Orr and Huda Y. Zoghbi independently discovered ATAXN1, the gene responsible for spinocerebellar ataxia 1 (SCA1), a disease in which neurons in the cerebellum degenerate and cause the loss of balance and coordination; it is progressive, permanent and often fatal. Working together, Orr and Zoghbi discovered that a similar repeat expansion causes SCA1 and discovered that the mutation caused proteins to misfold and clump together in cerebellar neurons, eventually leading to death. Additionally, Orr’s work showed the disease could be treated and his methodology is one of the main models being used for studying neurodegenerative diseases today.
Zoghbi also uncovered the gene MECP2, which causes Rett syndrome, a rare genetic neurological disorder that primarily presents in young girls, often with autism-like symptoms, and results in devastating motor and cognitive symptoms. Zoghbi discovered that changes in the level of MECP2, a repressor of gene expression is essential for the normal function of many types of neurons in the brain. MECP2 is one of the first identified epigenetic causes for a brain disorder. Her research found that MECP2 affects hundreds of neurons and genes and that normalizing MECP2 levels through oligonucleotide therapy reverses the gene’s effects.
Jean-Louis Mandel discovered an unusual mutation in a gene on the X chromosome that causes fragile X syndrome, an inherited form of intellectual disability, including autism and most commonly presents in males. He showed that the mutation was a string of triple-letter repeats that disrupted the FMR1 gene. Such repeats disrupt the transcription of the FMRP protein, which is vital for brain function. Today, “unstable repeat expansions” are recognized as a common disease mechanism responsible for more than 50 genetic disorders. A familiar pattern has also emerged: as the number of repeats increases with each generation, symptoms arise earlier and are more severe. Understanding these unstable repeat expansions provides a model for numerous neurological diseases. Mandel’s work led to improved diagnostic tools for fragile X.
Christopher A. Walsh discovered more than three dozen neurological disease genes, such as the “double cortex” syndrome, a rare neuronal migration disorder that presents with seizures and intellectual impairment and is seen almost exclusively in females. His research identified genetic mutations that underlie disorders affecting the cerebral cortex and can cause structural malformations that range from subtle to profound, including some forms of epilepsy and autism spectrum disorders. Many of these discoveries came from one of Walsh’s key innovations to study recessive mutations in geographically isolated families. In some of those children, Walsh made an intriguing discovery – mutations that were present in some but not all the cells of the body. They are called somatic mutations and can accumulate slowly during brain development.
The Kavli Prize is awarded by the Norwegian Academy of Science and Letters.
