A research team has uncovered a new mechanism involved in Bourneville tuberous sclerosis (BTS), a genetic disease of childhood. The team hypothesizes that a mutation in the TSC1 gene causes neurodevelopmental disorders that develop in conjunction with the disease.
Seen in one in 6,000 children, tuberous sclerosis causes benign tumours or lesions that can affect various organs such as the brain, kidneys, eyes, heart and skin. While some patients lead healthy lives, others have significant comorbidities, such as epilepsy, autism and learning disabilities.
Although the role that the TSC1 gene plays in the disease is already known, the scientists have only now identified a critical period in the postnatal development of GABAergic interneurons that are so important to the development of the brain. The results of their study are reported in Nature Communications.
All mammalian cells, and the proteins that form them, need a 'pathway' to regulate their individual growth, which scientists call a 'signaling pathway,' explained the first author of the new study.
"The signaling pathway of mTOR (mechanistic target of rapamycin) controls several aspects of the development of brain cells - the neurons - by regulating different metabolic processes: the proliferation, growth and mobility of neurons, as well as the biosynthesis and transcription of their proteins," the author said.
"The pathway is therefore pivotal in ensuring the development of neurons in an ideal environment."
When the mTOR signaling pathway is disrupted, certain diseases such as type-2 diabetes, obesity, neurodegeneration and cancer can occur.
"A mutation in the negative regulator of the TSC1 gene of the mTOR pathway is known to produce hyperactivation of the signaling pathway, resulting in abnormal cell proliferation," said the senior author.
"This disruption is responsible for neurodevelopmental disorders associated with autism, intellectual disability and epilepsy in tuberous sclerosis, but the underlying mechanisms were not well understood," said the author.
"Our original hypothesis was to see if this mutation in the mTOR pathway affected the development of GABAergic cells," said the author. "In many cases of autism, these cells are deregulated. However, in tuberous sclerosis, few studies have examined their involvement in the expression of neurological comorbidities."
Using an organotypic culture that mimics brain development (growth, maturation, and stabilization) ex vivo, the research team introduced the TSC1 gene mutation into GABAergic cells of mice at specific periods during their brain development.
Using biomarkers, the researchers found early and very rapid proliferation occuring in the growth phase of the mutated cells. Synaptic connections that form too quickly become 'defective' once they mature.
"We therefore have evidence that neurodevelopmental disorders are mediated by hyperactivity of the mTOR pathway caused by the absence of the TSC1 gene," said the author.
Rapamycin is a drug whose mechanism of action is related to the inhibition of the mTOR protein.
"By administering this protein in preclinical models - in this case, mice - we are able to 'rescue' synaptic connections and prevent neurodevelopmental disorders," said the author. "Based on our results, this therapeutic approach would be most appropriate to prevent premature maturation of neurons."
However, the author cautioned "since mTOR plays a very broad role in neuronal development, it is important to determine the exact timing of administration to avoid undesirable and possibly fatal results. We need to continue our research to confirm that these observations apply to humans."
https://www.nature.com/articles/s41467-021-23939-7
http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fsensitive-period-for&filter=22
Controlling neuronal hyperactivity in Bourneville's tuberous sclerosis
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