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IMPLICATIONS OF AN INTERACTION BETWEEN PINK1 AND VCP FOR PARKINSON’S DISEASE PATHOGENESIS

Steer, Erin K (2016) IMPLICATIONS OF AN INTERACTION BETWEEN PINK1 AND VCP FOR PARKINSON’S DISEASE PATHOGENESIS. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, and affects approximately 950 per 100,000 people in North America. The etiology of PD remains unknown, but a small percentage of affected individuals have heritable forms of the disease with known genetic causes. Study of the proteins encoded by these genes has provided tremendous insight into molecular pathways that underlie PD-associated neurodegeneration. Mutations in the gene encoding PTEN-induced kinase 1 (PINK1) have been identified as the cause of an autosomal, recessively inherited parkinsonism. PINK1 is a serine/threonine kinase, uniquely localized to both the cytosol and mitochondrion. The profound effect of PINK1 on mitochondrial homeostasis has been extensively investigated, but far less is understood about its function in the cytosol. This project aimed to identify cytosolic PINK1 interacting proteins and characterize the functional consequences of the association. Using an unbiased proteomic screen, valosin-containing protein (VCP), an AAA+ ATPase, was identified as a PINK1 interactor. Upon discovery that the physical association does not require mitochondrial localization, the role of VCP in previously identified functions of the cytosolic pool of PINK1 was examined. These studies discovered a PINK1-VCP pathway that promotes neurite extension and complexity, and contributes to the maturation and maintenance of synapses. Further, PINK1 and VCP were shown to co-regulate autophagy and the accumulation of high molecular weight ubiquitination products. These results indicate that the PINK1-VCP interaction plays a key role in dendritic arbor maintenance, synapse preservation, and autophagy regulation. These three processes are commonly impaired in sporadic and familial PD as well as other neurodegenerative diseases, indicating that treatments targeting components of the PINK1-VCP signaling hub may have broad therapeutic applications.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Steer, Erin Kerinkaysteer@gmail.comERS90
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorChu, Charleen T.ctc4@pitt.edu
Committee ChairKulich , Scott
Committee MemberKiselyov, Kirill
Committee MemberBrodsky, Jeffrey L
Committee MemberVodovotz, Yoram
Date: 20 May 2016
Date Type: Publication
Defense Date: 24 November 2015
Approval Date: 20 May 2016
Submission Date: 27 April 2016
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 148
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Cellular and Molecular Pathology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: VCP, PINK, Parkinson's disease, neuronal morphology
Date Deposited: 20 May 2016 15:19
Last Modified: 15 Nov 2016 14:33
URI: http://d-scholarship.pitt.edu/id/eprint/27842

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