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

Mittal, Shuchi ; Dubey, Deepti ; Yamakawa, Kazuhiro ; Ganesh, Subramaniam (2007) Lafora disease proteins malin and laforin are recruited to aggresomes in response to proteasomal impairment Human Molecular Genetics, 16 (7). pp. 753-762. ISSN 0964-6906

Full text not available from this repository.

Official URL: http://hmg.oxfordjournals.org/content/16/7/753.abs...

Related URL: http://dx.doi.org/10.1093/hmg/ddm006

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 γ-tubulin and cause redistribution of α-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.

Item Type:Article
Source:Copyright of this article belongs to Oxford University Press.
ID Code:102801
Deposited On:01 Feb 2017 17:35
Last Modified:01 Feb 2017 17:35

Repository Staff Only: item control page