Role of parkin in cytoprotection against misfolded SOD1 toxicity Open Access

Yung, Cheryl (2015)

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Amyotrophic lateral sclerosis (ALS) is a progressive neurological disease characterized by selective motor neuron death and accumulation of insoluble proteinaceous deposits in surviving motor neurons. Mutations in the antioxidant enzyme Cu/Zn superoxide dismutase (SOD1) cause ~20% of familial ALS cases. These mutations confer a toxic gain-of-function by inducing SOD1 misfolding and formation of cytotoxic SOD1 oligomers, which are sequestered into larger aggregates typical of ALS pathology. Misfolded proteins are normally efficiently handled by molecular chaperones and the ubiquitin-proteasome system, but when these protein quality control systems are impaired or overwhelmed, misfolded proteins can form soluble oligomers that are toxic to cells. The aggresome-autophagy pathway represents another cellular defense mechanism whereby cytotoxic oligomers are actively sequestered into a specialized type of perinuclear inclusion body known as the aggresome, where they are cleared by autophagy, a lysosome-dependent bulk degradation process. Although recent evidence indicates that misfolded SOD1 is targeted to perinuclear areas, forming aggresome-like inclusions, the mechanism responsible for this has not been identified. Our results show that parkin, an E3 ubiquitin-protein ligase linked to Parkinson disease, is a novel regulator of cellular defense against misfolded SOD1-induced cytotoxicity. We report that parkin mediates K63-linked polyubiquitination on mutant, but not wild-type, SOD1 and promotes misfolded SOD1 aggresome formation and clearance via the autophagy-lysosome system. Our findings reveal a novel role of parkin in cellular defense against misfolded SOD1 and suggests that targeting parkin may have therapeutic benefit for ALS.

Table of Contents

Chapter 1: Introduction and Background 1

Opening Comments 2

1.1 The ubiquitin system and protein degradation 4

Components of ubiquitin signaling 4

Ubiquitin-proteasome system 9

Autophagy-lysosome system 10

1.2 Protein misfolding in neurodegenerative disease 14

Aggresome-autophagy pathway 15

Parkinson disease 17

Disrupted ubiquitin signaling in PD 19

Amyotrophic lateral sclerosis 22

Ubiquitin dysregulation in ALS 26

1.3 Mouse models of neurodegenerative disease 30

PD mouse models 31

ALS mouse models 37

Mouse crossbreeding studies 43

1.4 Summary and organizational overview 46

1.5 Figures and Tables 48

Chapter 2: Parkin protects against misfolded SOD1 toxicity by promoting its aggresome formation and autophagic clearance 58

Abstract 59

2.1 Introduction 60

2.2 Results 63

2.3 Discussion 70

2.4 Materials & Methods 73

2.5 Figures & Legends 80

Chapter 3: Parkin deletion ameliorates disease phenotype in the SOD1G93A mouse model of amyotrophic lateral sclerosis 98

Abstract 99

3.1 Introduction 100

3.2 Results 102

3.3 Discussion 107

3.4 Materials & Methods 112

3.5 Figures & Legends 116

Chapter 4: Summary and Future Directions 132

4.1 Summary of findings 133

4.2 Implications of parkin function in ALS 135

4.3 Future Directions 139

4.4 Hypothesized model and closing comments 155

References 156

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