Disruption of protein-folding causes neurodegeneration, mental retardation

lled a lipid, is a critical component of normal neurons. But when the cell lacks beta-galactosidase, the enzyme needed for normal breakdown and recycling of GM1, this lipid accumulates and causes gangliosidosis.

Until now, the mechanism by which excess GM1 in lysosomes causes GM1 gangliosidosis was unknown. The St. Jude team demonstrated that the buildup of GM1 in the lysosomes causes a "back-up" of this lipid in the endoplasmic reticulum (ER) site where proteins are folded into their proper shape. This excess GM1 causes depletion of calcium, whose concentration in the ER is critical for proper protein folding. In turn, the accumulation of unfolded or improperly folded proteins triggers the unfolded protein response" (UPR) in the cell. The UPR is the cell's emergency response to the accumulation of faulty proteins. This response attempts to slow or halt new protein production and increase efforts to correct the folding of misfolded proteins. Over time, however, this emergency response may fail to cope with the stress, and the cell activates a self-destruct program and dies. As more and more brain cells die, the child suffers the symptoms of GM1 gangliosidosis.

"No one knew that the UPR cascade could be triggered by GM1 accumulation in the ER," said Alessandra Tessitore, Ph.D., formerly a senior research technician at St. Jude. "This finding was unexpected and an important step in the search for an effective treatment for GM1 gangliosidosis."

Tessitore is the first author of the Molecular Cell paper.

In the study, d'Azzo's team examined the spinal cords of mice that lacked the gene for beta-galactosidase, the enzyme also missing in children with GM1 gangliosidosis and responsible for breaking down GM1. The investigators found significantly more dying cells in spinal cords of mice missing the gene than in normal mice.

In addition, the St. Jude investigators studied the effect of adding large amounts of GM1 to normal cells called murine (mo

Contact: Bonnie Cameron
St. Jude Children's Research Hospital

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