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Author Notes:

Correspondence: xli2@emory.edu (X.-J.L.), sli@emory.edu (S.L.).

We thank the Transgenic Mouse & Gene Targeting Core at Emory University for generating MANF transgenic mouse model. We thank Dr. David Ron for his generous contribution of XBP1u and XBP1s plasmids and Cheryl Strauss for critical reading of this manuscript.


Research Funding:

The work was supported by the National Institutes of Health (grants AG19206 and NS041669 to X.-J.L. and AG031153 and NS0405016 to S.L.).

This research project was supported in part by the Viral Vector Core and the Emory University Integrated Cellular Imaging Microscopy Core of the Emory Neuroscience NINDS Core Facilities (grant P30NS055077) and the State Key Laboratory of Molecular Developmental Biology, China.


  • Aging
  • Analysis of Variance
  • Animals
  • Cells, Cultured
  • DNA-Binding Proteins
  • Disease Models, Animal
  • Estrogen Antagonists
  • Gene Expression Regulation
  • HSC70 Heat-Shock Proteins
  • Immunoprecipitation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation
  • Nerve Degeneration
  • Nerve Growth Factors
  • Peptides
  • Protein Kinase C
  • Purkinje Cells
  • TATA-Box Binding Protein
  • Tamoxifen
  • Transcription Factors

Age-dependent decrease in chaperone activity impairs MANF expression, leading to Purkinje Cell degeneration in inducible SCA17 Mice


Journal Title:



Volume 81, Number 2


, Pages 349-365

Type of Work:

Article | Post-print: After Peer Review


Although protein-misfolding-mediated neurodegenerative diseases have been linked to aging, how aging contributes to selective neurodegeneration remains unclear. We established spinocerebellar ataxia 17 (SCA17) knockin mice that inducibly express one copy of mutant TATA box binding protein (TBP) at different ages by tamoxifen-mediated Cre recombination. We find that more mutant TBP accumulates in older mouse and that this accumulation correlates with age-related decreases in Hsc70 and chaperone activity. Consistently, older SCA17 mice experienced earlier neurological symptom onset and more severe Purkinje cell degeneration. Mutant TBP shows decreased association with XBP1s, resulting in the reduced transcription of mesencephalic astrocyte-derived neurotrophic factor (MANF), which is enriched in Purkinje cells. Expression of Hsc70 improves the TBP-XBP1s interaction and MANF transcription, and overexpression of MANF ameliorates mutant TBP-mediated Purkinje cell degeneration via protein kinase C (PKC)-dependent signaling. These findings suggest that the age-related decline in chaperone activity affects polyglutamine protein function that is important for the viability of specific types of neurons.

Copyright information:

© 2014 Elsevier Inc.

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