The role of the E3 ubiquitin ligase FBXO7-SCF in early-onset Parkinson's disease

The role of the E3 ubiquitin ligase FBXO7-SCF in early-onset Parkinson's disease

Brockelt, David

Dissertation

Angenommen am: 2015-11-19

Erschienen: 2016-08-29

Betreuer: Stegmüller, Judith Dr.

Gutachter: Stegmüller, Judith Dr.

Gutachter: Outeiro, Tiago Fleming Prof. Dr.

Zum Verlinken/Zitieren: http://hdl.handle.net/11858/00-1735-0000-0028-881A-3

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Name: Doctoral Thesis David Brockelt.pdf

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Zusammenfassung

Englisch

Parkinson's disease (PD) is a debilitating movement disorder. Growing evidence associates genes with familial forms of the disease. Recently, gene mutations in the FBXO7 (PARK15) gene have been identified in patients with early-onset parkinsonism symptoms and pyramidal tract signs. PARK15 encodes for the E3 ubiquitin ligase FBXO7, whose function in the brain remains to be elucidated. In this study, I report that systemic loss of FBXO7 in mice results in an early-onset motor phenotype and premature death, reminiscent of the PARK15 patients. In neuropatholgical analyses, I find a regional increase in cell death and widespread astrogliosis. At the molecular level, I demonstrate the binding of FBXO7 to the proteasomal core subunit PSMA2 and identify PSMA as non-proteolytic ubiquitination substrate. Interestingly, I show that loss of FBXO7 in the brain leads to reduced proteasome activity as a consequence of defective proteasome integrity. Taken together, I established an FBXO7- dependent mechanism of proteasome regulation in neurons, which provides novel insight into the role of the UPS in PD.

Keywords: Biology