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Title: Endoplasmic reticulum structure and function in LRRK2-mediated Parkinson's disease
Author: Nixon-Abell, J. J.
ISNI:       0000 0004 8499 665X
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2017
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The endoplasmic reticulum (ER) is a continuous, membranous network extending from the nuclear envelope to the outer periphery of cells, playing crucial roles in numerous cellular functions. The intricate structural arrangement of the ER is governed by a group of ER-shaping proteins, with mutations in associated genes known to influence ER morphology. Aberrant ER function has been well documented in various neurodegenerative disorders, however the detailed characterisation of mechanistic and structural changes that occur under pathogenic conditions remain poorly understood. I employed superresolution (SR) and electron microscopy with complementary biochemical techniques to examine detailed ER morphology and the maintenance of this structure by associated proteins. Mutations in leucine-rich repeat kinase 2 (LRRK2) represent a large genetic contributor to familial Parkinson's disease (PD). I demonstrate herein that the interaction between LRRK2 protein and a family of ER-shaping proteins known as reticulons (RTNs) plays an important role in maintaining ER shape. In the brains of LRRK2 null mice, I found architectural abnormalities in the ER and an elevation in ER stress markers. I propose a loss of LRRK2-RTN interaction as a probable mediator of this ER phenotype. In endeavouring to understand how ER structure is affected in disease states, I made several critical observations that have significant implications for ER biology in healthy cells. With a specific focus on the ER towards the periphery of cells, I used emerging SR techniques to characterize a novel structure now termed an ER matrix. These structures have been misidentified with conventional imaging technologies due to the remarkable complexity of ER structure, and a previously uncharacterized form of rapid ER motion. Taken together, I explored links between ER structure, dynamics and function and their important implications for both basic cell biology and neurodegenerative pathogenesis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available