Human Molecular Genetics Advance Access originally published online on May 23, 2008
Human Molecular Genetics 2008 17(16):2570-2582; doi:10.1093/hmg/ddn157
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Autophagy-mediated clearance of aggresomes is not a universal phenomenon
1 Neurodegeneration Research Laboratory, National Neuroscience Institute, Singapore 2 Raffles Junior College, Singapore 3 University College London, London WC1E 6BT, UK 4 Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, Wako, Saitama, Japan 5 Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA 6 Department of Anatomy and Structural Biology, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, New York, USA 7 Duke-NUS Graduate Medical School 8 Department of Biological Sciences, National University of Singapore, Singapore
* To whom correspondence should be addressed at: Neurodegeneration Research Laboratory, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433. Tel: +65 63577520; Fax: +65 62569178; Email: kah_leong_lim{at}nni.com.sg/kahleong.lim{at}gms.edu.sg
Received February 22, 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 
-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 composition of inclusions, ‘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.
These authors contributed equally.
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