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Human Molecular Genetics Advance Access published online on May 23, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn157
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Autophagy-mediated clearance of aggresomes is not a universal phenomenon

Esther S.P. Wong1,6, Jeanne M.M. Tan1, Wen-E Soong1,2, Kamila Hussein1,3, Nobuyuki Nukina4, Valina L. Dawson5, Ted M. Dawson5, Ana Maria Cuervo6,# and Kah-Leong Lim1,7,8,#,*

1 Neurodegeneration Research Lab, National Neuroscience Institute, Singapore 2 Raffles Junior College, Singapore 3 University College London, United Kingdom 4 Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, Japan 5 Institute for Cell Engineering, Johns Hopkins University School of Medicine, U.S.A 6 Department of Anatomy and Structural Biology, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, USA 7 Duke-NUS Graduate Medical School 8 Department of Biological Sciences, National University of Singapore, Singapore

* To Whom All Correspondence Should Be Addressed: Kah-Leong Lim, Ph.D. Neurodegeneration Research Laboratory, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433Tel: (65)-6357-7520 Fax: (65)-6256-9178 E-mail: Kah_Leong_Lim{at}nni.com.sg

Received February 22, 2008; Revised May 20, 2008; Accepted May 20, 2008

Aggresomes are juxtanuclear inclusion bodies that have been proposed to act as staging grounds for the disposal of protein aggregates via the autophagic route. To examine whether the composition of an aggresome influences its clearance by autophagy, we ectopically expressed a variety of aggregation-prone proteins in cultured cells to generate aggresomes that differ in their protein content. We found that whereas aggresomes generated in cells expressing mutant huntingtin or mutant tau, or co-expressing synphilin-1 and {alpha}-synuclein are amenable to clearance by autophagy, those produced in AIMP2 (p38)- or mutant desmin-expressing cells are apparently resistant to autophagic clearance. Notably, AIMP2 (p38)- and desmin-positive inclusions fail to recruit key components of the autophagic/lysosomal system. However, by altering the inclusions composition, "autophagy-resistant" aggresomes could be rendered "autophagy-susceptible". Taken together, our results demonstrate that not all aggresomes are efficiently primed for autophagic clearance and highlight a certain degree of selectivity for the supposedly non-discriminative pathway.

# Authors contributed equally


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