Human Molecular Genetics Advance Access first published online on November 25, 2008
This version published online on December 1, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn398
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The malin-laforin complex suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system
Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, India
* Corresponding author: Subramaniam Ganesh, Ph.D., Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India, Tel: +91-512-259-4040, Fax: +91-512-259-4010, Email: sganesh{at}iitk.ac.in
Received August 16, 2008; Revised November 12, 2008; Accepted November 19, 2008
Lafora disease (LD), a progressive form of inherited epilepsy, is associated with widespread neurodegeneration and the formation of polyglucosan bodies in the neurons. Laforin - a protein phosphatase, and malin - an E3 ubiquitin ligase, are two of the proteins that are defective in LD. We have shown recently that laforin and malin (referred together as LD proteins) are recruited to aggresome upon proteasomal blockade, possibly to clear misfolded proteins through the ubiquitin-proteasome system. Here we test this possibility using a variety of cytotoxic misfolded proteins, including the expanded polyglutamine protein, as potential substrates. Laforin and malin, together with Hsp70 as a functional complex, suppress the cellular toxicity of misfolded proteins, and all the three members of this complex are required for this function. Laforin and malin interact with misfolded proteins and promote their degradation through the ubiquitin-proteasome system. LD proteins are recruited to the polyglutamine aggregates and reduce the frequency of aggregate-positive cells. Taken together, our results suggest that the malin-laforin complex is a novel player in the neuronal response to misfolded proteins and could be potential therapeutic targets for neurodegenerative disorders associated with cytotoxic proteins.
# The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors
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