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Retromer Deficiency in Amyotrophic Lateral Sclerosis

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Retromer Deficiency in Amyotrophic Lateral Sclerosis Retromer deficiency in amyotrophic lateral sclerosis Eduardo J Pérez-Torres Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy under the Executive Committee of the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2020 © 2020 Eduardo J Pérez-Torres All Rights Reserved ABSTRACT RETROMER DEFICIENCY IN AMYOTROPHIC LATERAL SCLEROSIS Eduardo J Pérez-Torres The retromer is a protein complex whose function is to mediate the recycling of proteins from the endosome to either the plasma membrane or the trans-Golgi network. A deficit in retromer function has been associated with multiple neurodegenerative disorders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). In both AD and PD, deficiencies have been found in retromer expression both in patient tissues and in animal models of disease. Furthermore, mutations in the retromer and in retromer-associated genes have been strongly linked with both diseases. Despite ample evidence of the link between the retromer and neurodegeneration, little is known about the retromer in the context of amyotrophic lateral sclerosis (ALS), another common neurodegenerative disorder. ALS is an adult-onset neurodegenerative disorder of the upper and lower motor neurons (MNs) characterized by muscle wasting and weakness leading to death within 3-5 years after diagnosis. To date, the most commonly used model of ALS is a transgenic (Tg) mouse that overexpresses an ALS-causing G93A mutation in the human superoxide dismutase 1 (SOD1) gene. In this study, I first establish a link between the retromer and ALS by showing that cells from ALS patients as well as tissues and cells from SOD1G93A-Tg mice express lower protein levels of the retromer core components—vacuolar protein sorting 35 (Vps35), Vps26a, and Vps29. I then establish that deficiencies in retromer core proteins have functional consequences in an in vitro model of ALS. Having found significant deficiencies in the retromer in SOD1G93A-Tg mice, I then followed the model of studies performed in mouse models of other neurodegenerative disorders by investigating whether repletion of retromer levels, either virally or pharmacologically, in SOD1G93A-Tg mice confers a therapeutic benefit. Surprisingly, I find that rather than ameliorating disease, repletion of retromer levels in SOD1G93A-Tg mice exacerbates it, resulting in a faster decline in motor performance, earlier mortality, and a decrease in MNs in the spinal cord. Finally, since retromer repletion causes deleterious effects on SOD1G93A-Tg mouse disease progression, I study the effect of a single allele deletion of Vps35 in SOD1G93A-Tg mice and find that this depletion of the retromer results in amelioration of disease, including delayed onset of symptomatology, slower decline of motor deficits, delayed mortality, and an increase in MNs in the spinal cord. Altogether, the findings reported herein, support the notion that a mild defect in retromer develops over the course of the disease, which, rather than being deleterious may be therapeutic in mutant SOD1-induced MN degeneration. Perhaps this unexpected outcome may be explained by the fact that the observed mild nature of the defect is not sufficient to kill MNs but enough to alter the trafficking of specific cargos such as AMPA receptors, allowing MNs to better withstand the neurodegenerative process. TABLE OF CONTENTS List of Figures and Tables.............................................................................................................. iv Acknowledgements ....................................................................................................................... vii Chapter 1 General Introduction ...................................................................................................... 1 1.1 Endosomal trafficking ........................................................................................................... 1 1.1.1 Endocytosis..................................................................................................................... 2 1.1.2 Golgi-to-Endosome Transport ........................................................................................ 4 1.1.3 Endosomal Maturation ................................................................................................... 5 1.1.4 Macroautophagy ........................................................................................................... 13 1.1.5 Recycling ...................................................................................................................... 16 1.2 Retromer in Neurodegenerative Disease ............................................................................. 27 1.2.1 Alzheimer’s Disease ..................................................................................................... 27 1.2.2 Parkinson’s Disease ...................................................................................................... 31 1.2.3 Other Neurological Disorders....................................................................................... 34 1.3 Amyotrophic Lateral Sclerosis ............................................................................................ 37 1.3.1 Clinical features of ALS ............................................................................................... 38 1.3.2 Neuropathology of ALS ............................................................................................... 42 1.3.3 Familial ALS and associated mutations ....................................................................... 44 1.3.4 Mouse models of ALS .................................................................................................. 46 1.3.5 Disease mechanisms of ALS ........................................................................................ 50 1.4 Specific Aims ...................................................................................................................... 63 Chapter 2 Retromer Quantification in Cells and Tissues from ALS Patients and Mouse Models of ALS ............................................................................................................................................... 65 2.1 Introduction ......................................................................................................................... 65 2.2 Results ................................................................................................................................. 67 2.2.1 Characterization of retromer expression in SOD1G93A-Tg mouse tissues .................... 67 2.2.2 Characterization of retromer expression in ALS-affected neural cells in the SOD1G93A- Tg mouse ............................................................................................................................... 74 2.2.3 Characterization of retromer expression in ALS-affected human tissues and cells ..... 80 2.3 Discussion ........................................................................................................................... 87 2.3.1 Retromer depletion in ALS MNs ................................................................................. 87 2.3.2 Retromer depletion in ALS astrocytes ......................................................................... 89 2.3.3 Retromer depletion coincides with active ALS pathology ........................................... 90 i 2.3.4 Expression of retromer proteins and mRNAs in ALS tissues and cells ....................... 92 2.3.5 Retromer deficiency not specific to mutations in SOD1 .............................................. 94 Chapter 3 Causes and Effects of Retromer Deficiency in SOD1G93A-Tg Astrocytes In Vitro ..... 96 3.1 Introduction ......................................................................................................................... 96 3.1.1 Degradation of retromer proteins ................................................................................. 96 3.1.2 Retromer trafficking of APP ........................................................................................ 97 3.2 Results ................................................................................................................................. 98 3.2.1 Retromer expression is independent of astrocyte activation state ................................ 99 3.2.2 Retromer degradation rate is independent of astrocyte SOD1G93A transgene expression ............................................................................................................................................. 100 3.2.3 APP trafficking and processing in SOD1G93A-Tg astrocytes ...................................... 102 3.2.4 Neurotoxicity due to retromer depletion in an in vitro system ................................... 106 3.3 Discussion ......................................................................................................................... 110 3.3.1 Retromer protein degradation ..................................................................................... 110 3.3.2 APP processing in ALS .............................................................................................. 111 3.3.3 Neurotoxicity of retromer depletion ........................................................................... 113 Chapter 4 Retromer Repletion in SOD1G93A-Tg mice ................................................................ 114 4.1 Introduction ......................................................................................................................
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