Increased susceptibility of cytoplasmic over nuclear polyglutamine aggregates to autophagic degradation
- 2 September 2005
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 102 (37) , 13135-13140
- https://doi.org/10.1073/pnas.0505801102
Abstract
CNS neurons are endowed with the ability to recover from cytotoxic insults associated with the accumulation of proteinaceous aggregates in mouse models of polyglutamine disease, but the cellular mechanism underlying this phenomenon is unknown. Here, we show that autophagy is essential for the elimination of aggregated forms of mutant huntingtin and ataxin-1 from the cytoplasmic but not nuclear compartments. Human orthologs of yeast autophagy genes, molecular determinants of autophagic vacuole formation, are recruited to cytoplasmic but not nuclear inclusion bodies in vitro and in vivo . These data indicate that autophagy is a critical component of the cellular clearance of toxic protein aggregates and may help to explain why protein aggregates are more toxic when directed to the nucleus.Keywords
This publication has 44 references indexed in Scilit:
- Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal deathNature, 2004
- Emerging Role for Autophagy in the Removal of Aggresomes in Schwann CellsJournal of Neuroscience, 2003
- Formic Acid Dissolves Aggregates of an N-Terminal Huntingtin Fragment Containing an Expanded Polyglutamine Tract: Applying to Quantification of Protein Components of the AggregatesBiochemical and Biophysical Research Communications, 2000
- Huntingtin Expression Stimulates Endosomal–Lysosomal Activity, Endosome Tubulation, and AutophagyJournal of Neuroscience, 2000
- Reversal of Neuropathology and Motor Dysfunction in a Conditional Model of Huntington's DiseaseCell, 2000
- Glutamine Repeats and NeurodegenerationAnnual Review of Neuroscience, 2000
- The Endosomal-Lysosomal System of Neurons in Alzheimer's Disease Pathogenesis: A ReviewNeurochemical Research, 2000
- The Role of Multiubiquitination in Dislocation and Degradation of the α Subunit of the T Cell Antigen ReceptorJournal of Biological Chemistry, 1999
- Caspase activation during apoptotic cell death induced by expanded polyglutamine in N2a cellsNeuroReport, 1999
- Dispersion, aberration and deconvolution in multi‐wavelength fluorescence imagesJournal of Microscopy, 1996