Organoids reveal similarities between myotonic dystrophy type 1 and Rett syndrome

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Myotonic type 1 dystrophy (DM1) is the most common type of muscular dystrophy, which involves progressive muscle damage and results in repetitive DNA sequences written in RNA cells. poisons. Instead of carrying out the instructions of the cell to translate into proteins, these RNA molecules accumulate in the cells, disrupting the cellular machinery.

Rett (RS) is a rare disease of the genes that affects the way the brain develops, resulting in the continued loss of motor skills and language in early life.

Text in the online issue of June 29, 2022 Science InterpretationResearchers at the University of California San Diego School of Medicine used three-dimensional brain cells derived from added cells which mimics nerve functions — to find out the exact similarities between DM1 and RS, and perhaps therapeutic potential.

“We turned to 3D brain tumors that mimic human brain cells to study the effects of CTG repetitive strain on neuronal pathways,” said lead author Kathryn Morelli, Ph.D. author Gene Yeo, Ph.D. .D., Professor of cellular and antibiotics at UC San Diego School of Medicine.

“It is a process that can be performed from strong cell lines generated by actual DM1 patients carrying these toxic RNA concentrations. It mimics cortical growth in utero.”

Unlike other types of muscular dystrophy, patients with DM1 often show signs of neurocognitive development, with learning and social problems that may appear similar to autism spectrum disorders. Recent clinical data suggest that the higher the amount of inherited DNA, the greater the early onset of symptoms — and the greater the impact of the disease on the central nervous system.

Modern DM1 treatments are only aimed at skeletal and muscle damage. Studies by Yeo and colleagues have shown that CRISPR / Cas target RNA-binding proteins can bind to repetitive RNA in living cells and reverse signaling pathways in the skeletal muscle of DM1 mice.

“Still, the lack of a cellular model of the human brain limits our understanding of how toxic RNA can lead to cognitive symptoms, and hinders efforts to improve treatment efficiency,” Morelli said.

In the new study, the researchers collected a small amount of RNA targeted CRISPR / Cas in the cells, and then added them to the DM1 brain cells. They found that the proteins destroyed a collection of toxic RNA, with scientists being able to monitor and control the events.

The team focused on a product in which toxic RNA captures a specific type of protein called RNA bind proteins, or RBPs. “In cortical organoids, we were surprised to find that an RBP called CELF2 protein is dysregulated in glutamatergic neurons, which are responsible for signaling in the brain,” Yeo said.

Using improved coordination mechanisms and immunohistochemistry that was first developed in the laboratory, Morelli and colleagues found that CELF2 did not bind to its common target: molecules in methyl-CpG binding. protein Method 2 (MECP2) which are essential for neuron function. Mutations that result in loss of normal MECP2 function result in RS.

The findings, according to the authors, suggest a possible association in defects in neurodegenerative development in DM1 and RS. Morelli noted that clinical trials are being conducted to evaluate the potential therapeutic N-methyl-d-aspartic acid (NMDA) antagonists for the treatment of patients with RS. NMDA receptors are believed to be important in synaptic plastic processing and intermediate learning and brain function.

In DM1 organoids, Morelli found that anti-NMDA receptors altered the pathogenesis of the disease, suggesting that targeted NMDA receptors may improve cognition in young patients with DM1, and improve their quality of life.

Authors include Wenhao Jin, Shashank Shathe, Assael A. Madrigal, Krysten L. Jones, Joshua L. Schwartz, Tristan Bridges, Jasmine R. Mueller, Archana Shankar, Isaac A. Chaim, all at UC San Diego; and John W. Day, Stanford University.

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Learn more:
Kathryn H. Morelli et al, MECP2-related pathways are degraded in the organoid cortical structure of myotonic dystrophy, Science Interpretation (2022). DOI: 10.1126 / scitranslmed.abn2375

hintOrganoids describe similarities between type 1 myotonic dystrophy and Rett syndrome (2022, June 29) restored 29 June 2022 from myotonic-dystrophy.html

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