Lafora disease proteins malin and laforin are recruited to aggresomes in response to proteasomal impairment.

Abstract

Lafora disease (LD), an autosomal recessive neurodegenerative disorder, is characterized by the presence of cytoplasmic polyglucosan inclusions known as Lafora bodies in several tissues including the brain. Laforin, a protein phosphatase, and malin, an ubiquitin ligase, are two of the proteins that are known to be defective in LD. Malin interacts with laforin and promotes its polyubiquitination and degradation. Here we show that malin and laforin co-localize in endoplasmic reticulum (ER) and that they form centrosomal aggregates when treated with proteasomal inhibitors in both neuronal and non-neuronal cells. Laforin/malin aggregates co-localize with gamma-tubulin and cause redistribution of alpha-tubulin. These aggregates are also immunoreactive to ubiquitin, ubiquitin-conjugating enzyme, ER chaperone and proteasome subunits, demonstrating their aggresome-like properties. Furthermore, we show that the centrosomal aggregation of laforin and malin is dependent on the functional microtubule network. Laforin and malin form aggresome when expressed together or otherwise, suggesting that the two proteins are recruited to the centrosome independent of each other. Taken together, our results suggest that the centrosomal accumulation of malin, possibly with the help of laforin, may enhance the ubiquitination of its substrates and facilitate their efficient degradation by proteasome. Defects in malin or laforin may thus lead to increased levels of misfolded and/or target proteins, which may eventually affect the physiological processes of the neuron. Thus, defects in protein degradation and clearance are likely to be the primary trigger in the physiopathology of LD.

• Authors: Shuchi Mittal, Deepti Dubey, Kazuhiro Yamakawa, Subramaniam Ganesh
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 16 Issue 7 Pg. 753-62 (Apr 01 2007) ISSN: 0964-6906 [Print] England
• PMID: 17337485 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• Cysteine Proteinase Inhibitors
• Leupeptins
• Recombinant Fusion Proteins
• Tubulin
• Ubiquitin
• lactacystin
• Green Fluorescent Proteins
• NHLRC1 protein, human
• Ubiquitin-Protein Ligases
• Protein Tyrosine Phosphatases
• Protein Tyrosine Phosphatases, Non-Receptor
• EPM2A protein, human
• Proteasome Endopeptidase Complex
• benzyloxycarbonylleucyl-leucyl-leucine aldehyde
• Acetylcysteine

Topics

• Acetylcysteine (analogs & derivatives, pharmacology)
• Animals
• COS Cells
• Carrier Proteins (genetics, metabolism)
• Cell Line
• Cell Line, Tumor
• Centrosome (metabolism)
• Chlorocebus aethiops
• Cysteine Proteinase Inhibitors (pharmacology)
• Endoplasmic Reticulum (metabolism)
• Green Fluorescent Proteins (genetics, metabolism)
• Humans
• Immunoblotting
• Immunohistochemistry
• Inclusion Bodies (metabolism)
• Lafora Disease (metabolism)
• Leupeptins (pharmacology)
• Microscopy, Fluorescence
• Proteasome Endopeptidase Complex (metabolism)
• Protein Binding (drug effects)
• Protein Tyrosine Phosphatases (genetics, metabolism)
• Protein Tyrosine Phosphatases, Non-Receptor
• Recombinant Fusion Proteins (genetics, metabolism)
• Transfection
• Tubulin (metabolism)
• Ubiquitin (metabolism)
• Ubiquitin-Protein Ligases