Cell Type-Dependent Activities of the Ubiquitin-Proteasome System and Selective Neurodegeneration Open Access

Tydlacka, Suzanne (2009)

Permanent URL: https://etd.library.emory.edu/concern/etds/9p2909884?locale=en
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Abstract


Cell type-dependent activities of the ubiquitin-proteasome system and selective
neurodegeneration

By Suzanne Tydlacka
A variety of neurological disorders and polyglutamine (polyQ) diseases are caused by
misfolded proteins. The common feature of these diseases is late-onset cellular
degeneration that selectively affects neurons in distinct brain regions. PolyQ diseases,
including Huntington's disease (HD), present a clear case of selective neurodegeneration
caused by polyQ expansion-induced protein misfolding, which leads to predominant
inclusions in neuronal nuclei. It remains unclear how these ubiquitously expressed
disease proteins selectively kill neurons. In HD, mutant huntingtin accumulates in both
neurons and astrocytes, but more neuronal cells display huntingtin aggregates. These
aggregates colocalize with components of the ubiquitin-proteasome system (UPS), which
plays a critical role in clearing misfolded proteins. Using fluorescent reporters that
reflect cellular UPS activity, we found that UPS activity in neurons and astrocytes
decrease in a time-dependent manner. Neuronal UPS activity is lower than astrocytic
UPS activity, which is consistent with the more abundant htt aggregates in neuronal cells.
Similarly, in the nucleus and synapses in which mutant htt accumulates, UPS activity is
also lower than that in the cell body. Moreover, inhibiting the UPS markedly increases
the accumulation of mutant htt in cultured astrocytes. These findings suggest that
differential UPS activities are dependent on cell types as well as subcellular localization
and account for the preferential accumulation of misfolded proteins in neurons and their
selective vulnerability.

Table of Contents

CHAPTER 1: GENERAL INTRODUCTION 9

1.1 Huntington's Disease 11 1.2 Misfolded and Aggregated Proteins in Huntington's Disease 12 1.3 The Ubiquitin-Proteasome System 13 1.4 Ubiquitin-Proteasome System in Polyglutamine Diseases 14 1.5 Aging of the Ubiquitin-Proteasome System 16 1.6 Available Tools to Study the Ubiquitin-Proteasome System 17 1.7 Mouse Models of Huntington's Disease 20 1.8 Hypothesis 22 CHAPTER 2: USE OF PROTEASOME REPORTERS TO MEASURE 24 UBIQUITIN-PROTEASOME SYSTEM ACTIVITY 2.1 Abstract 25 2.2 Introduction 26 2.3 Materials and Methods 28 2.4 Results 32 2.5 Discussion 35 CHAPTER 3: UBIQUITIN-PROTEASOME SYSTEM ACTIVITY IN CULTURED NEURONS AND GLIA 38 3.1 Abstract 39 3.2 Introduction 41 3.3 Materials and Methods 43 3.4 Results 48 3.5 Discussion 53 CHAPTER 4: UBIQUITIN-PROTEASOME SYSTEM ACTIVITY IN NEURONS AND ASTROCYTES IN HD KNOCK-IN MICE BRAINS 56 4.1 Abstract 57 4.2 Introduction 58 4.3 Materials and Methods 60 4.4 Results 64 4.5 Discussion 67 CHAPTER 5: UBIQUITIN PROTEASOME ACTIVITY IN NEURONAL SYNAPSES 69 5.1 Abstract 70 5.2 Introduction 71 5.3 Materials and Methods 73 5.4 Results 78 5.5 Discussion 80 CHAPTER 6: CONCLUSIONS AND FUTURE DIRECTIONS 83 6.1 Summary of Key Findings 84 6.2 Implications 84 6.3 Interpretation 86 6.4 Remaining Questions and Future Directions 88 REFERENCES 92-100 FIGURE CAPTIONS 101-132 FIGURES AND TABLES: AT THE END OF THE DISSERTATION 133-163

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