Modification in Huntingtin Protein Prolongs Survival, Improves Lung Function in Rett Mouse Model, Study Finds

A specific modification made in the huntingtin protein, which plays a key role in brain development, was able to improve motor and lung function and prolonged the survival in a mouse model of Rett syndrome, a study has found.

In particular, this alteration promotes the transport of brain-derived neurotrophic factor (BDNF) — a protein that plays a key role in nerve cell survival and development.

The study, “Huntingtin phosphorylation governs BDNF homeostasis and improves the phenotype of Mecp2 knockout mice,” was published in the journal EMBO Molecular Medicine.

Rett syndrome is caused by mutations in the MECP2 gene, which provides instructions to make MeCP2 protein. This protein controls the activity of several genes, including the gene with  instructions to make BDNF.

BDNF is necessary for the survival and development of neurons in the brain. Low BDNF levels in the brain have been associated with the onset and progression of Rett symptoms in mouse models.

In previous studies, when scientists used genetic manipulation to boost BDNF production in the brains of mice lacking the MeCP2 protein, the animals’ symptoms were only partially alleviated. These findings suggested that an overall increase in BDNF levels in the brain may be insufficient to enable significant improvements, because the appropriate nerve cells are not specifically targeted.

Other studies reported that transport of BDNF in nerve cells is mediated by huntingtin, previously found to be at very low levels in specific neurons of MeCP2-deficient mice, a model that mimics the symptoms of Rett syndrome.

In this study, researchers from the Aix Marseille University in France and their collaborators looked at whether activating huntingtin would be sufficient to restore BDNF transport in certain nerve cells, and to ease symptoms and extend survival of MeCP2-deficient mice.

The investigators used a man-made device to mimic the corticostriatal brain pathway in a lab dish. This pathway plays a key role in goal-directed behaviors, cognition, and motor control.

Results showed that the transport of BDNF in axons, which are extensions of neurons responsible for the transmission of electrical signals, was very slow in nerve cells genetically modified to lack MeCP2.

They discovered that a chemical modification to add a phosphate group — a process called phosphorylation — to the amino acid serine at position 421 of huntingtin had a direct impact on BDNF transport. (Amino acids are the building blocks of proteins).

More specifically, they showed that this modification activated huntingtin, which, in turn, restored the transport of BDNF in nerve cells both in vitro (in the lab dish) and in mice without MeCP2.

The team also showed that altering huntingtin either by genetic or pharmacological approaches prolonged survival, reduced weight loss, and improved both motor and lung function in the Rett mouse model, even though treatment started after animals were showing signs of the disease.

“We conclude that BDNF trafficking and supply are diminished in the absence of Mecp2 and can be effectively stimulated by promoting HTT [huntingtin] phosphorylation,” the investigators wrote. “Stimulation of endogenous cellular pathways may thus be a promising approach for the treatment of RTT [Rett] patients.”