Abstract
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)
About this Dissertation
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