The University of Texas Health Science Center at San Antonio
11/20/2024 | News release | Distributed by Public on 11/20/2024 09:33
Trailblazing neuroscientist studies cognitive deficits in Duchenne muscular dystrophy
Duchenne muscular dystrophy is the most common form of childhood muscular dystrophy and one of the most severe forms of inherited muscular dystrophy. The x-linked genetic condition causes mutations in the dystrophin gene that leads to progressive muscle weakness. Typically affecting boys, it occurs in about every 1 in 3,500 to 5,000 male births, with around 15,000 to 20,000 people living with this condition in the United States and about 300,000 worldwide.
Most children with this condition are diagnosed by age two or three, in a wheelchair by age 12, and, by their mid- to late 20s, most individuals die, usually due to heart or respiratory failure.
Jason Pugh, PhD, professor in the Department of Cellular and Integrative Physiology, Joe R. and Teresa Lozano Long School of Medicine, The University of Texas Health Science Center at San Antonio (UT Health San Antonio), is redefining how we understand the devastating impacts of Duchenne muscular dystrophy - starting with the brain.
A neuroscientist with a passion for unraveling the intricate nature of synaptic transmission, Pugh said that just seven years ago he knew next to nothing about Duchenne muscular dystrophy. In 2015, he received a Max and Minnie Tomerlin Voelcker Fund Young Investigator Award, which was pivotal to his pursuit of this research path, he said. The fund supports young scientists who conduct research on a handful of diseases, one of which is muscular dystrophy. Since then, he has become a pioneer in the little-explored frontier of cognitive dysfunctions connected to this form of muscular dystrophy.
Dystrophin's role in the brain
In the more than three decades of study on Duchenne muscular dystrophy, there has been a wealth of information about the role of dystrophin in muscle tissue but almost nothing about its function in neurons, the nerve cells that receive and transmit messages to and from the body and the brain.
Pugh said when he began studying Duchenne muscular dystrophy, scientists had deduced that dystrophin had a part to play in inhibitory synapses, but what that role had remained unclear.
Duchenne muscular dystrophy's cognitive symptoms continue to be largely unexplored. Pugh said symptoms can manifest as lower IQ scores, deficits in verbal or working memory and other neurodevelopmental disorders. In fact, up to 20% of people with Duchenne muscular dystrophy are also diagnosed with autism spectrum disorder, attention-deficit/hyperactivity disorder or obsessive-compulsive disorder.
"There's something going on in the central nervous system. It turns out that dystrophin is also expressed in certain types of neurons, and the highest expression anywhere in the brain is in the Purkinje cells of the cerebellum," Pugh said.
Purkinje cells are output neurons in the cerebellar cortex that play an important role in coordination, movement, learning and emotion. This connection between Duchenne muscular dystrophy's cognitive dysfunction and dystrophin expression in Purkinje cells is what piqued Pugh's interest in this condition since much of his previous work focused on these cells.
Pugh holds two prestigious NIH R01 grants to investigate how dystrophin deficiency in Purkinje cells may drive cognitive deficits and comorbidities in Duchenne muscular dystrophy. On top of that, he's leading an unrelated R01 project studying how endocannabinoid receptors regulate synaptic plasticity, which, in an interesting twist, may also be a treatment target for enhancing cognitive function in people with Duchenne muscular dystrophy. With just 4% of researchers holding three or more R01s, Pugh is in elite scientific territory.
Dystrophin's effects on inhibitory synapses
Pugh said the current goal for his lab is to understand what dystrophin does in Purkinje neurons and what happens to these synapses and circuits when dystrophin is lost.
Under his previous grant the lab discovered that when dystrophin is depleted there is a massive reduction in the number of inhibitory synapses, which, together with excitatory synapses, modulate the activity of downstream neurons, he explained. "The next step, is to find out why this happens and what exactly dystrophin is doing in this process."
In one of Pugh's studies, he hypothesized that dystrophin in the brain is necessary for synapse maturation and without it, synapses will fail to fully mature.
"Early in development, synapses are forming, but they are not maturing. We are seeing that most of these synapses remain in an immature state," Pugh said.
Without the signaling between the pre- and post-synaptic components, enabled by dystrophin, these components are not maturing as they would normally. Pugh said eventually these immature synapses will fall apart and disappear.
What comes next?
Pugh said with the progress in the treatment of muscle symptoms, people with muscular dystrophy may one day be able to live longer, fuller lives. Advances in care have already helped some individuals live into their 30s and 40s. The future of muscular dystrophy study, he said, may be an increased focus on what this disease is doing in the brain and how it can be treated.
Pugh is a clear frontrunner in the study of dystrophin's role in cognitive deficits related to this baffling disease. Only a couple of other labs in the United States are doing similar work and he hopes the field will expand in the future.
Managing multiple studies means endless paperwork and challenges, but for Pugh, it's all worth it. He's fueled by the possibility that his research at UT Health San Antonio could one day change the lives of thousands of children with Duchenne muscular dystrophy.