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Master Gene May Hold Key To Treating Lysosomal Storage Disorders

September 12, 2011

Earlier this year, an international consortium of researchers showed that a master gene called transcription factor EB or TFEB controls both the mechanism by which debris is gathered up in cell and that which destroys it.

In a report in the current issue of the journal Developmental Cell, Dr. Andrea Ballabio, scientific director at the Telethon Institute of Genetics and Medicine in Naples Italy, and a professor of molecular and human genetics at Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute at Texas Children´s Hospital along with his colleagues have found that TFEB also regulates exocytosis of lysosomes — a process in which these intracellular machines act as a dump truck, taking the debris to the inner surface of the cell and fusing with its membrane to dump debris outside the cells.

Getting rid of abnormal buildup

Cells need to be able to rid themselves of the debris that collects after important activities. When this debris piles up in the cell, it can clog the cell, preventing it from carrying out its important activities. When the lysosomes that carry out the destruction process fail, diseases such as Tay Sachs, Batten and Fabry result, causing disability and even death in children born with the disorder. In adults, the failure of this system may lead to neurodegenerative diseases such as Alzheimer´s or Parkinson´s.

In this study, the researchers found that increasing the level TFEB draws more lysosomes to the cell membrane and also improves their ability to fuse there. When the researchers increased the amount of TFEB in cell models of diseases associated with defects in debris removal (lysosomal storage disorders), they were “rescued.” In other words, the increased number of lysosomes rid the cells of the abnormal buildup of debris.

“Our findings demonstrate that lysosomal exocytosis is regulated by TFEB,” said Ballabio.

The findings will have to be verified in animals to determine if this phenomenon can be used as a treatment.

New way to treat neurodegenerative disorders?

“These findings do suggest an alternative strategy to treat LSDs (lysosomal storage disorders) and common neurodegenerative disorders,” said Ballabio.

Others who took part in this research include Diego L. Medina and Alessandro Fraldi, who are the co-first authors of the manuscript, , Valentina Bouche, Fabio Annunziata, Gelsomina Mansueto, Carmine Spampanato, Claudia Puri, Antonella Pignata, and Roman Polishchuk, all of the Telethon Institute of Genetics and Medicine in Naples, Marco Sardiello and Michela Palmieri, both of BCM and the Jan and Dan Duncan Neurological Research Institute at Texas Children´s, and Jose A. Martina and Rosa Puertollano, both of the National Heart, Lung and Blood Institute in Bethesda, Maryland.

Funding for this work came from the Italian Telethon Foundation, the European Research Council, the European Commission, the Beyond Batten Disease Foundation and the National Heart, Lung and Blood Institute of the National Institutes of Health.

The laboratory at the NRI is a joint venture between the Telethon Foundation, the Jan and Dan Duncan Neurological Research Institute at Texas Children´s and BCM.

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