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Author Notes:

Correspondence should be addressed to either Shihua Li or Xiao-Jiang Li, Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322. E-mail: sli@emory.edu,xli2@emory.edu.

X.-J.L., T.Z., and S.L. designed research.

T.Z., Y.H., and S.L. performed research.

X.-J.L., T.Z., Y.H., and S.L. analyzed data.

X.-J.L., T.Z., and S.L. wrote the paper.

We thank the Integrated Cellular Imaging Core at Emory University for the use of imaging facilities and Cheryl Strauss for critical reading of this manuscript.

The authors declare no competing financial interests.

Subjects:

Research Funding:

This work was supported by National Institutes of Health Grants AG19206 and NS041449 (X.-J.L.) and AG031153 and NS045016 (S.L.), and the National Natural Science Foundation of China (91332206 to X.J.L.).

Keywords:

  • clearance
  • degradation
  • misfolding
  • neurodegeneration
  • polyglutamine
  • subcellular

Compartment-dependent degradation of mutant huntingtin accounts for its preferential accumulation in neuronal processes

Tools:

Journal Title:

Journal of Neuroscience

Volume:

Volume 36, Number 32

Publisher:

, Pages 8317-8328

Type of Work:

Article | Final Publisher PDF

Abstract:

In neurodegenerative diseases caused by misfolded proteins, including Huntington’s disease (HD), the neuronal processes and terminals are particularly prone to the accumulation of misfolded proteins, leading to axonal and synaptic dysfunction. This compartmentdependent accumulation can result from either the altered transport of misfolded proteins or impaired protein degradation. Mutant huntingtin (mHtt), the HD protein, is known to affect intracellular transport and can be degraded by the proteasome and autophagy, but how mHtt accumulates in the neuronal processes, an early pathological event in the brains of HD patients, still remains unclear. Using an “optical pulse-chase” assay that can quantify protein degradation in specific subcellular regions, wefound that neuronal mHtt is removed faster in the cell body than in neurites. Furthermore, mHtt is cleared more rapidly in astrocytes than in neurons. The ubiquitinproteasome system plays a much bigger role than autophagy in degrading soluble mHtt via K48 ubiquitination in both the cytoplasm and processes of neurons and astrocytes. By injecting adenoviral vectors expressing mHtt into the mouse brain, we confirmed that mHtt is removed more slowly in neurites than in the cytoplasm of the cell body of neurons. Our findings provide evidence for the cell type- and compartment-dependent degradation of mHtt and explain why mHtt preferentially accumulates and aggregates in the neuropils of vulnerable neurons. In addition, our findings suggest that enhancing proteasomal activity could be an effective way to reduce the preferential accumulation of soluble mHtt in neuronal processes.

Copyright information:

© 2016 the authors.

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