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KLC1 Deficiency Alters APP and Tau Levels and Impairs Neuronal Development

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KLC1 Deficiency Alters APP and Tau Levels and Impairs Neuronal Development UNIVERSITY OF CALIFORNIA, SAN DIEGO KLC1 deficiency alters APP and tau levels and impairs neuronal development A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Biomedical Sciences by Rhiannon Lynn Killian Committee in charge: Professor Lawrence S. B. Goldstein, Chair Professor Don W. Cleveland Professor Marilyn G. Farquhar Professor Edward H. Koo Professor Jean Y. J. Wang 2011 The Dissertation of Rhiannon Lynn Killian is approved, and it is acceptable in quality and form for publication on microfilm and electronically: Chair University of California, San Diego 2011 iii DEDICATION As the culmination of six years of unceasing effort, I can do no other but dedicate this work to my children, Patrick, Killian and Conley, who I hope will one day understand why I was in the laboratory when they awoke and ‘too busy’ when at home. iv EPIGRAPH It is a popular delusion that the scientific enquirer is under an obligation not to go beyond generalization of observed facts...but anyone who is practically acquainted with scientific work is aware that those who refuse to go beyond the facts, rarely get as far. Thomas Henry Huxley (1825-95) English biologist We are in the ordinary position of scientists of having to be content with piecemeal improvements: we can make several things clearer, but we cannot make anything clear. Frank Plumpton Ramsey (1903-1930) English mathematician For a successful technology, reality must take precedence over public relations, for Nature cannot be fooled. Richard Feynman (1918-1988) American physicist v TABLE OF CONTENTS DEDICATION .............................................................................................................. iv EPIGRAPH ..................................................................................................................... v TABLE OF CONTENTS .............................................................................................. vi LIST OF FIGURES ..................................................................................................... viii ACKNOWLEDGEMENTS .......................................................................................... ix VITA ............................................................................................................................... x ABSTRACT OF THE DISSERTATION ...................................................................... xi CHAPTER 1 ................................................................................................................... 1 Introduction .................................................................................................................... 1 Kinesin-1 structure and function ............................................................................ 1 Alzheimer’s Disease (AD) and axonal transport defects ....................................... 4 Modeling aspects of AD in mouse and man ........................................................... 7 References ................................................................................................................ 12 CHAPTER 2 ................................................................................................................. 19 Kinesin-1C and KLC1 affect neuronal development and APP levels in murine hippocampal neurons .................................................................................................... 19 Abstract ..................................................................................................................... 19 Introduction .............................................................................................................. 21 Materials and Methods ............................................................................................. 23 Preparation of primary mouse hippocampal cultures ........................................... 23 Analysis of hippocampal axons ............................................................................ 23 Immunofluorescence characterization of primary mouse hippocampal cultures . 24 Western blot analysis of protein levels. ................................................................ 25 Quantification of A β/P3 ....................................................................................... 26 Results and Discussion ............................................................................................. 27 Murine KLC1 and Kinesin-1C protein levels in primary hippocampal cultures are related ................................................................................................................... 27 Kinesin-1C and KLC1 may function in hippocampal neuron development ........ 29 Tau levels are unchanged in primary hippocampal neurons with reduced KLC1. .............................................................................................................................. 30 Altered extracellular A β/p3 levels in Kinesin-1C-/- hippocampal cultures ......... 32 Characterization of KLC1-/- and Kinesin-1C-/- hippocampal primary cultures .. 34 Conclusions .............................................................................................................. 35 References ................................................................................................................ 44 CHAPTER 3 ................................................................................................................. 48 Kinesin light chain 1 reduction impairs human embryonic stem cell neural differentiation and amyloid precursor protein metabolism .......................................... 48 Abstract ..................................................................................................................... 48 Introduction .............................................................................................................. 49 Materials and Methods ............................................................................................. 51 vi Cell culture and subcloning of undifferentiated Hues9 hESC lines ..................... 51 Flow cytometry ..................................................................................................... 52 Western blot analysis of protein levels ................................................................. 53 Immunofluorescence ............................................................................................ 54 Neural differentiation of hESC ............................................................................. 55 Brightfield imaging of cultures ............................................................................ 56 Neural precursor culture, viral transduction and differentiation .......................... 56 Aβ and soluble APP (sAPP) quantification .......................................................... 57 Results ...................................................................................................................... 57 KLC1 reduction does not alter hESC morphology or pluripotency ..................... 57 KLC1 depleted hESC produce cultures containing neural precursors (NPs) ....... 58 Neural precursors with reduced KLC1 do not proliferate normally ..................... 60 KLC1-deficient human neural cells exhibit reduced levels of microtubule related proteins ................................................................................................................. 61 Reduced KLC1 alters APP metabolism in human neural cultures derived from hESC ..................................................................................................................... 65 Discussion ................................................................................................................. 66 A role for the KLC1 subunit of Kinesin-1 in NP maintenance? .......................... 66 KLC1 depletion affects microtubule associated proteins ..................................... 68 Effect of KLC1 reduction on APP metabolism in human neural cultures. .......... 69 Summary ................................................................................................................... 71 Acknowledgements .................................................................................................. 71 References ................................................................................................................ 89 CHAPTER 4 ................................................................................................................. 94 Discussion ..................................................................................................................... 94 Co-regulation of KLC1 and Kinesin-1C protein levels ........................................ 94 Roles for KLC1 (and Kinesin-1C) in neural development ................................... 96 Tau and Kinesin-1 subunits KLC1 and Kinesin-1C ........................................... 102 Does Kinesin-1C regulate APP levels and metabolism by controlling APP transport? ............................................................................................................ 105 Model for KLC1 functions in neural development and in regulating neuronal Tau and A β levels. ..................................................................................................... 111 Prospects for human pluripotent stem cell based systems for modeling human development, biology and disease .....................................................................
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