Research Highlight

Chaperone targets for Lafora disease

doi:10.1038/nindia.2010.164 Published online 24 November 2010

Researchers have found potential therapeutic targets for Lafora disease, a fatal genetic condition caused by the presence of inclusion bodies, known as Lafora bodies, in cells of the heart, liver, muscle and skin. These targets could be the molecular chaperones Hsc70 and Hsp70. Molecular chaperones are proteins that help to restore the native states of proteins when they are destabilized by external stress.

Lafora disease is caused by mutations in either the EPM2A gene, which encodes the protein phosphatase laforin, or the EPM2B gene, which encodes the ubiquitin ligase malin. However, how mutations in these two genes trigger Lafora disease is not well understood.

The researchers found that Lafora bodies in the axillary skin and brain of patients stained positively for the ubiquitin, 20S proteasome and the molecular chaperones Hsp70/Hsc70. In skin biopsy samples of these patients, they also found the malin mutants that form aggregates in cell culture and are associated with Lafora bodies. Overexpression of mutant malin induced proteasomal dysfunction and cell death. On the other hand, chaperone overexpression reduced aggregation of mutant malins and protected malin-induced cell death.

The findings suggest that Lafora bodies consist of abnormal proteins, including mutant malin, targeted by the chaperones or the proteasome for their refolding or clearance. Failure of these quality control systems could lead to the onset of Lafora disease. This also indicates that the chaperones could be potential therapeutic targets for addressing Lafora disease.


  1. Rao, S. N. R. et al. Sequestration of chaperones and proteasome into Lafora bodies and proteasomal dysfunction induced by Lafora disease-associated mutations of malin. Hum. Mol. Genet. 19, 4726-4734 (2010) | Article | PubMed