Problems in how nerve cells degrade waste may underlie Rett, study finds
Autophagy, a cell cleansing process, seen as impaired in disease mouse model
Defects in how cells degrade old or damaged components, a cellular recycling process called autophagy, contribute to the dysfunction of nerve cells in Rett syndrome, a lab study reports.
Treating mice in a Rett disease model with trehalose, a naturally occurring molecule known to induce autophagy, restored the recycling process and improved nerve cell function, as well as the animals’ motor and exploratory skills. Its use also eased anxiety-like behaviors.
“We believe that our data constitute a proof of principle for the investigation of novel therapies to treat devastating neurodevelopmental disorders, such as [Rett], based on the concept of autophagy enhancement,” the researchers wrote.
The study, “Unraveling autophagic imbalances and therapeutic insights in Mecp2-deficient models,” was published in the EMBO Molecular Journal.
Research into how autophagy fails in cells in a Rett model
Nearly all cases of Rett are caused by mutations in the MECP2 gene, which encodes the MeCP2 protein. These mutations disrupt the MeCP2’s activity, impairing the function of synapses, the connections between nerve cells, to cause disease symptoms.
Autophagy is a process whereby cells break down old, damaged, or abnormal proteins, lipids (fats), and other substances, to either be reused or discarded. When activated by cellular signals, a key step in autophagy is the formation of the autophagosome, a membrane-bound sac that encircles and captures cellular waste. This structure then fuses with lysosomes, other sacs containing digestive enzymes that break down the waste.
Because nerve cells have relatively long lives, autophagy plays an essential role in maintaining their health and integrity. Accordingly, problems with autophagy in nerve cells are associated with neurodegenerative diseases and neurodevelopmental disorders.
Studies also report the buildup of cellular material failing to be degraded in the brains of Rett patients.
Researchers at institutes in Milan, Italy, investigated autophagy in a Rett syndrome model lacking Mecp2, the mouse version of the disease-causing gene.
Experiments showed these mice had fewer that normal autophagic sacs within nerve cells, which correlated with defects in LC3B-II lipidation, a process essential for autophagosome formation. LC3B-II lipidation involves the attachment of a lipid called phosphatidylethanolamine to the LCB-I protein, generating LC3B-II, which supports the growing autophagosome membrane.
Lysosome fusion, the process wherein these structures acquire cargo for degradation, was unaffected.
In line with these findings, the team found lower-than-normal amounts of LC3B-II in skin cells from a Rett patient.
“These data suggest that the biogenesis of new autophagosomes is impaired in Mecp2 [deficient] neurons, and this relates to a defect in the conversion of LC3B-I to LC3B-II,” the researchers wrote.
Further work revealed that the defect in LC3B-II lipidation in nerve cells was due to a lack of phosphatidylethanolamine compared with healthy mice, serving as controls. Consistently, supplementation with ethanolamine, a component of that lipid, restored LC3B-II lipidation.
Trehalose, an autophagy activator, helped restore movement and behavior
Researchers then tested how a naturally occurring sugar-like molecule called trehalose affected diseased mice and their nerve cells. Trehalose is known to be a potent activator of autophagy, as it promotes LC3B-II lipidation.
In Rett nerve cells, treatment with trehalose restored phosphatidylethanolamine levels and ameliorated autophagy-related defects, improving nerve cell function and synaptic structure.
Mice given trehalose displayed better motor function and exploratory behaviors, and reduced anxiety-related features. Treated healthy mice showed no affects, supporting trehalose’s safety.
“Our findings strengthen the hypothesis that dysfunctions of autophagy and related signaling pathways, such as lipid metabolism, might represent previously neglected molecular mechanisms that contribute to [Rett development],” the researchers concluded.
“By gaining comprehension of [the] defective autophagic cascade in Mecp2-deficient models, we pose novel therapeutic perspectives for Rett syndrome and for other neurodevelopmental disorders based on the concept of autophagy modulation,” they wrote.
Future studies, the team added, should investigate treating female mice in a Rett model — “which better represent the genetic condition of [Rett] patients, even though they manifest a milder phenotype [disease characteristics]” — with trehalose, and testing trehalose and other autophagy modulators in nerve cells derived from patients’ stem cells.
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