The Rett syndrome (RTT) is a neurodevelopmental disorder that affects 1 out of 10,000 girls. They present a neurodevelopment disruption affecting language, cognition and motor function.  The RTT is caused, in the 90 – 95% of the cases, by mutations of MECP2, a gene that controls the transcription of other genes.

A team of scientists noticed that the skin fibroblasts from RTT patients, isolated and cultivated in laboratory, showed difficulties in growing when “fed” with few nutrients. Moreover, the same fibroblasts and the Red Blood Cells (RBCs) taken from RTT patients presented signs of oxidative stress and a reduced content in ATP, i.e., they had an impairment of the energy production. In other words, these cells had difficulties in regulating their homeostasis.

The presence of such alterations led the scientists to investigate the possible intracellular “clues” linked to the impairments observed. More concretely, they focused in the macroautophagy, that is, the degradation of those intracellular organelles (via intermediate structures called autophagosomes) which become unnecessary or damaged under stressful conditions, for example, nutrient scarcity, heat, oxidative stress. Also, the macroautophagy has an important role in various processes of the development of the central nervous system, as the arborization of the dendritic spine.

Impairment of the macroautophagy in RTT fibroblasts

The authors of the paper here summarized made grow fibroblast isolated from RTT patients in conditions of nutrient scarcity and compared their behavior with that of healthy fibroblasts cultivated at the same conditions. First of all, only 40% of the RTT fibroblasts survived after 10 hours of starvation, while the percentage of survival was of 90% in the healthy fibroblasts. So, the RTT fibroblasts underwent an early process of programmed cell death, called apoptosis.

Then, they observed that the RTT cells were unable to perform the macroautophagy, so that, they could not form the autophagosomes to send the unnecessary organelles to the lysosomes in order to be degraded and eliminated. On the contrary, the healthy fibroblasts presented a number of autophagosomes. The conclusion is that the patients with RTT suffer the block of the macroautophagy.

Presence of mitochondria in mature RTT RBCs

RBCs are well known for their lack of the nucleus; nevertheless, they also lack mitochondria. The loss of the mitochondria occurs during the final stages of the RBCs maturation through a process of autophagy. The authors of the study hypothesized that the RBCs taken from RTT patients might not have completely eliminated the mitochondria, due to the impairment of the autophagic process.

The analysis of RTT and healthy RBCs by transmission electron microscopy confirmed their hypothesis: the RBCs from RTT patients showed the presence of some organelles similar to mitochondria. Those structures looked like mitochondria, both intact and morphologically altered. This finding is particularly important because it confirms the results of other studies that showed the same morphologic alterations of mitochondria in the muscular and cerebellum cells of the RTT patients. So, the altered autophagy seems to be a hallmark of the RTT in the cellular phenotype (as also confirmed in similar observation in the cerebellum of mice lacking the MECP2 gene).

Final remarks

The results of the study suggest that the impairment of the autophagy mechanisms at the cellular level is one of the main causes of the RTT phenotype although, at the moment, there is not a certain and direct relationship with the mutations of the MECP2 gene yet. Further studies are required, but the research on cell autophagy is a promising way to develop future therapeutic strategies.


Sbardella D. et al. Retention of Mitochondria in Mature Human Red Blood Cells as the Result of Autophagy Impairment in Rett Syndrome. Scientific Reports | 7: 12297 | DOI:10.1038/s41598-017-12069-0

The elaboration of this post has been financed by the project PI15/01082, as a part of the National Plan of I+D+I and co-financed by the ISCIII – General Deputy Direction for Evaluation and Development of Health Research – and the European Regional Development Fund (ERDF).