Autophagy malfunction study moves a step closer to understanding Rett syndrome microbiologystudy

Rett syndrome is a rare genetic disease affecting 1 in 10,000 newborn girls, characterized by sudden regression around 1 year of age, with loss of acquired language and motor skills and leading to profound cognitive impairment. Its main cause is mutations of the gene MeCP2, an important controller of neuronal development in the brain.

Precisely for being a master controller, it has been difficult to decipher how exactly MeCP2 loss of function leads to the many alterations observed within the affected brain cells, like morphological abnormalities and synaptic imbalances. New research from the Regulatory RNA and Chromatin lab at the Josep Carreras Institute sheds light on one of these alterations: autophagy malfunction.

The inner life of a cell is highly dynamic and it needs to get rid of obsolete components quite often: proteins no longer needed, organelles that expanded for a specific task, etc. One of the systems the cell uses to fulfill this task is autophagy, literally “to eat oneself,” and it is an important part of the cell’s maintenance. Defects in the autophagy system lead to the accumulation of protein aggregates and other deficiencies within the cell, resulting in abnormal function and potentially dire consequences.

In the research, first-authored by Dr. Edilene Siqueira and recently published in the journal Nucleic Acids Research, the team used the latest genetic tools available, such as single-cell RNA sequencing and CRISPR/Cas9 gene editing technology, and found that mutations in MeCP2 led to the depletion of a long non-coding RNA called NEAT1.

As it turns out, NEAT1 controls the autophagy system by establishing direct RNA-RNA contacts with components of its machinery and directing their localization within the cell. Consequently, NEAT1 deficiency contributes to some of the cellular alterations found in Rett syndrome.

Furthermore, the team demonstrated that restoring NEAT1 could reverse these alterations in in vitro models of the disease, opening the door to the exploration of new therapeutic approaches in the coming years.

The research is a joint effort between the Regulatory RNA and chromatin group headed by Dr. Sònia Guil, researchers from the Cancer Epigenetics laboratory led by Dr. Manel Esteller, also in the Josep Carreras Institute, the Bellvitge Biomedical Research Institute (IDIBELL) and the Hospital Sant Joan de Déu.