Ubiquitin C-terminal hydrolase regulation and dysfunction in neurodegenerative disease pathogenesis Open Access

McKeon, Jeanne E. (2014)

Permanent URL: https://etd.library.emory.edu/concern/etds/sb397843p?locale=en


Mutations in the gene encoding ubiquitin C-terminal hydrolase L1 (UCH-L1) are linked to familial Parkinson disease (PD) and neurodegeneration with optic atrophy in humans as well as gracile axonal dystrophy in mice. UCH-L1 is observed in Lewy body deposits and soluble UCH-L1 protein is reduced in sporadic PD brain. However, mechanisms regulating the UCH-L1 level and the role UCH-L1 loss-of-function plays in neurodegenerative disease pathogenesis remain unknown. In my dissertation work, I investigated the association between UCH-L1 and parkin, an E3 ubiquitin protein ligase commonly mutated in autosomal recessive PD. I found evidence in vitro and in vivo showing that parkin regulates the lysosomal degradation of UCH-L1 via polyubiquitination. Next, to examine the effect of UCH-L1 loss-of-function on the maintenance and structure of peripheral nerves, I assessed axonal distributions in the L4 dorsal root, L4 ventral root, and sciatic nerve of UCH-L1 deficient mice. I also assessed sensory and motor nerve conduction from these animals. My data support an age-dependent distal-to-proximal mode of primary axonal degeneration in the peripheral nervous system of UCH-L1 deficient mice. Together the work described in this dissertation reveals a novel mechanism regulating UCH-L1 protein level with relevance to PD pathogenesis, and demonstrates, for the first time, functional deficits in peripheral nerves corresponding with axonal degeneration and phenotype severity resulting from UCH-L1 loss-of-function.

Table of Contents

Chapter 1: Introduction and Background (1) Opening Comments (2) 1.1 The ubiquitin system and regulation of protein turnover (4) Ubiquitination machinery and ubiquitin signaling (4) Deubiquitinating enzymes (DUBs) (5) DUB Families (6) Role of ubiquitin signaling in the regulation of protein degradation in mammalian cells (9) 1.2 Disrupted ubiquitin signaling in neurological diseases (13) Parkinson disease (13) Peripheral sensory and motor neuropathies (15) Neurodegeneration observed in UCH-L1 null mice (21) Potential role of UCH-L1 in synaptic function (24) 1.5 Role of parkin in neurodegenerative disease pathogenesis (26) Parkin is commonly mutated in autosomal recessive PD (26) Parkin structure and catalytic mechanism (28) Mutant parkin pathogenicity (30) 1.6 Summary and organizational overview (32) 1.7 Figures and Tables (35) Chapter 2: Parkin-mediated K63-polyubiquitination targets ubiquitin C-terminal hydrolase L1 for degradation by the autophagy-lysosome system (40) Abstract (41) 2.1 Introduction (42) 2.2 Experimental Procedures (44) 2.3 Results (48) 2.5 Figures (57) Chapter 3: UCH-L1 is required for maintenance and function of sensory and motor axons in the peripheral nervous system 69 Abstract (70) 3.1 Introduction (71) 3.2 Experimental Procedures (72) 3.3 Results (76) 3.4 Discussion (80) 3.5 Figures (84) Chapter 4: Summary, Implications, and Future Directions (95) 4.1 Summary of findings (96) 4.2 Insight into UCH-L1 function in health and disease (98) Implications for Parkinson disease (98) Implications for peripheral sensory and motor neuropathies (101) Comments on UCH-L1 gain of function vs loss of function in conferring different neurodegenerative disease outcomes (104) Implications for cancer pathogenesis (106) 4.3 Future Directions (108) Does PINK1 phosphorylation of parkin stimulate the ubiquitination of UCH-L1? (108) What are other mechanisms that regulate the UCH-L1 protein? (110) Does UCH-L1 regulate axonal transport? (111) 4.4 Hypothesized model of UCH-L1 dysfunction in neurological disease and closing remarks (113) References (116)

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