Functional analysis of the  parkinsonism-associated protein FBXO7 (PARK15) in neurons

Functional analysis of the parkinsonism-associated protein FBXO7 (PARK15) in neurons

Guergana Ivanova Dontcheva

Doctoral thesis

Date of Examination: 2017-06-23

Date of issue: 2017-09-07

Advisor: Stegmüller, Judith Dr.

Referee: Brose, Nils Prof. Dr.

Referee: Stoykova, Anastassia Prof. Dr.

Referee: Outeiro, Tiago Fleming Prof. Dr.

Persistent Address: http://hdl.handle.net/11858/00-1735-0000-0023-3EF5-7

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Abstract

English

Parkinson's disease (PD) is a debilitating neurodegenerative disease affecting the elderly population. It has been a challenge elucidating the molecular mechanisms underlying the selective loss of dopaminergic neurons, since much of the etiopathology of the disease remains unknown. Genetic studies of the familial PD cases have yielded a handful of Parkinson's related loci- the PARK loci, that have attributed most of the molecular knowledge we have. In this study, I investigated the role of PARK15- the FBXO7 protein in neurons at the molecular, cellular and histological level. I found that FBXO7 interacts with the microtubule associated protein 1B light chain 1 (MAP1B LC1) independently of its E3-ligase activity. Furthermore, FBXO7 is an important factor in mitochondrial maintenance and it is essential for neuronal morphogenesis. Quantitative mass spectrometry supported this data and further expanded the involvement of FBXO7 in multiple cellular mechanisms such as DNA repair and vesicular transport. Additionally, I examined the effect of knockout of Fbxo7 in the forebrain in Mus musculus, and observed a generalized brain damage without the loss of cortical neurons. Taken together, these findings further broaden our understanding of the pathological mechanisms leading to neuronal death in PD patients.

Keywords: FBXO7; Parkinson's Disease; PARK15; UPS; Mitochondria; MAP1B LC1