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Identifier 000396123
Title Role of the S18Y polymorphism of UCH-L1 protein on neuroprotection
Alternative Title Ο ρόλος του πολυμορφισμού S18Y της πρωτεϊνης UCH-L1 στην νευροπροστασία
Author Καμαράτου, Μαρτίνα
Thesis advisor Καραγογέως, Δ.
Γραβάνης, Α.
Reviewer Στεφανής, Λ.
Abstract Parkinson’s disease (PD) is a chronic neurodegenerative disease and the second most common neurological disorder after Alzheimer disease. It is characterized by motor and non motor symptoms. Τhe main motor symptoms include tremor at rest, slowness or absence of voluntary movement, rigidity (increased resistance to passive movement of patient’s limbs) and freezing. The neuropathological hallmarks of PD are the progressive loss of the dopaminergic neurons in the substantia nigra pars compacta and the presence of intraneuronal proteinacious deposits within the surviving neurons, termed Lewy Bodies. The majority of PD cases (95%) are sporadic, whereas only 5% of cases are familiar. As far as sporadic PD is concerned, evidence implicates mitochondrial damage, dysfunction of protein degradation systems, oxidative stress and inflammation in disease development. For the familiar forms of PD, several dominant and recessive inheritance genes have been linked to the disease. PARK-5 locus is one of the PD-linked genes with an autosomal dominant manner of inheritance and codes for the protein UCH-L1. UCH-L1 belongs to the Ubiquitin C- terminal Hydrolase family and is the only member of this family reported to dimerize. It is one of the most abundant proteins in the brain and is localized in the pre- and postsynaptic regions. It is also normally expressed in testes and ovaries. Experimental evidence suggests that UCH-L1 protein possesses hydrolase and ligase activity in vitro. In has been also reported to bind to mono-ubiquitin in vitro, thus inhibiting its degradation and stabilizing its intracellular levels. Although UCH-L1 is abundant in neuronal cells, the physiological role of this protein in vivo remains elusive. The genetic linkage of UCH-L1 protein to PD was reported in 1998, when the I93M mutation in the UCH-L1 gene was found in a German family with autosomal dominant PD. The S18Y UCH-L1 polymorphism was discovered in 1999 and reported to be protective against sporadic forms of PD, a finding that has been questioned by many studies, while others suggest an age-dependent protective effect. Even though the S18Y UCH-L1 polymorphism was recently found to exert a neuroprotective role against well-established oxidants, such as MPP+ and H2O2, the precise mechanism via which this is accomplished, remains elusive. The aim of the present study was to examine the mechanism of the potential neuroprotective effects of the S18Y UCH-L1 protein in neuronal cells. Using the double farnesylation mutant S18Y [10] C220S UCH-L1, which is reported to bind to a lower extent to membranes, we found that inhibition of farnesylation did not alter the membrane binding or the protective effect of the S18Y polymorphism against MPP+-induced toxicity. In addition, overexpressed S18Y UCH-L1 protein localized at similar levels in cytosol, nuclei, mitochondria and endosomes, compared to overexpressed WT UCH-L1, under normal conditions. In an attempt to investigate whether the protective properties of S18Y polymorphism are selective against oxidative stress-evoked insults or might be observed, against other neurotoxic stimuli, we found that S18Y UCH-L1 was not protective against excitotoxic cell death induced by L-Glutamate, or neurotoxicity mediated by α-synuclein overexpression. These results suggest that the S18Y UCH-L1 polymorphism exerts a specific anti-oxidant neuroprotective role. Since S18Y UCH-L1 localized both in lysosomes and mitochondria, organelles known to contribute to the regulation of redox homeostasis, this protein may exert a protective effect following its translocation to one of these compartments, upon oxidative stress conditions. As oxidative stress is implicated in pathophysiology of PD and other neurodegenerative conditions, the elucidation of the mechanism(s) mediating the observed anti-oxidant effect of the S18Y UCH-L1 protein, may pave the way for the development of new therapeutic strategies for the treatment of PD and related disorders.
Language English
Subject Oxidative stress
Parkinson's disease
Νόσος Parkinson
Οξειδωτικό στρες
Issue date 2015-07-17
Collection   School/Department--School of Medicine--Department of Medicine--Post-graduate theses
  Type of Work--Post-graduate theses
Permanent Link https://elocus.lib.uoc.gr//dlib/b/a/a/metadata-dlib-1441706512-433906-9368.tkl Bookmark and Share
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