Therapeutic effect of Berberine on Huntington's Disease Transgenic Mouse Model Open Access

Jiang, Wenxiao (2015)

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Huntington's Disease (HD) is an incurable autosomal dominant, debilitating neurodegenerative disease caused by a CAG trinucleotide repeat expansion in exon 1 of the huntingtin (Htt) gene, which encodes a polyglutmine (polyQ) repeat tract in the Nterminal Htt. The disease is characterized by neurological symptoms such as chorea, dystonia, bradykinesia, dementia, and normally affects the mid-elderly. In severe cases, HD can onset at a much younger age because of large polyQ repeat expansions that are often in excess of 55 glutamines. Pathologically, HD is hallmarked by the formation of mutant Htt (mHtt) aggregate accumulation in the brain and neurodegeneration that preferentially affects the striatum. HD affects roughly 30,000 patients in the US, mostly of Western-European descent. Although there are efforts to treat HD by stemming and ameliorating its symptoms, so far, no treatments have been successful at preventing or delaying the development of this devastating disease. Berberine (BBR) is an abundantly-available, botanically-derived organic small molecule that is traditionally used orally to treat bacterial diarrhea and is well-tolerated in humans both in chronic and high-dosage use. Recently, BBR has shown protective effects on neurodegenerative conditions such as Alzheimer's Disease and Parkinson's Disease, which sparked our interest in the possible effects of BBR against HD. In this study, we show that BBR treatment reduces mHtt aggregation both in a transfected cell model and in the brains of a transgenic HD mouse model via up-regulation of autophagic clearance of mutant proteins. The HD mice exhibited drastically improved motor function and a slightly increased lifespan. These encouraging results on HD mouse models also provide mechanistic insight into the broad effects of BBR on neurodegenerative diseases caused by misfolded aggregated proteins.

Table of Contents

Chapter 1: Introduction 1

1.1 Huntington's Disease 2

1.2 Huntington's Disease Research 4

1.3 Huntingtin Aggregation and Huntington's Disease 7

1.4 Defense Mechanisms Against Protein Aggregation 9

1.5 Berberine 12

1.6 Berberine and Neurodegenerative Diseases 13

1.7 Berberine and Huntington's Disease 21

1.8 Summary of Aims and Results of Study 22

Chapter 2: Therapeutic Potential of Berberine Against

Neurodegenerative Disease 39

2.1 Abstract 40

2.2 Introduction 41

2.3 Therapeutic Effect of Berberine on Alzheimer's Disease 42

2.4 Therapeutic Effect of Berberine on Parkinson's Disease 44

2.5 General Neurprotective Effects of Berberine 47

2.6 Effects of Berberine on Common Pathways in

Neurodegeneration 48

2.7 Conclusion 50

2.8 References 56

Chapter 3: Therapeutic Effect of Berberine on

Huntington's Disease Transgenic Mouse Model 65

3.1 Abstract 66

3.2 Introduction 67

3.3 Materials and Methods 68

3.4 Results 76

3.5 Discussion 81

3.6 Acknowledgements 104

3.7 References 104

Chapter 4: Final Discussion 113

4.1 Summary 114

4.2 Interpretation and Significant of Results 115

4.3 Future Studies 118

4.4 Conclusion 122

References 125


Chapter 1: Introduction

Table 1-1 Symptom Prevalence in Clinically-Evaluated cases of Huntington's Disease 27

Table 1-2 CAG Repeat Size Correlated with Age of Onset 29

Figure 1-1 Neurodegeneration in the Brain of Huntington's Disease Patients 31

Figure 1-2 Model for Mutant Protein Aggregate Formation 33

Figure 1-3 Molecular Structure of Berberine 35

Figure 1-4 Known Anti-Neurodegenerative Properties of Berberine 37

Chapter 2: Therapeutic Potential of Berberine Against Neurodegenerative Disease

Figure 1 Molecular Structure of Berberine 52

Figure 2 Known Anti-Neurodegenerative Properties of Berberine 54

Chapter 3: Therapeutic Effect of Berberine on Huntington's Disease Transgenic Mouse Model

Figure 1 BBR reduced Htt aggregation in vitro in a dose and time-dependent manner 85

Figure 2 BBR increases autophagic activity in cultured cells 90

Figure 3 Oral administration of BBR ameliorates neurologicalsymptoms in transgenic N171-82Q mice 94

Figure 4 Oral administration of BBR reduced mutant Htt ggregation and increased autophagy in transgenic N171-82Q mice 100

Chapter 4: Final Discussion

Figure 4-1 Model for Berberine's Role in Mutant Huntingtin Aggregate Accumulation 123

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