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Title: The molecular cell biology of spartin
Author: Edwards, T. L.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2008
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This thesis has focused on the protein spartin, which is mutated in a form of autosomal recessive hereditary spastic paraplegia (HSP) called Troyer syndrome. Upon commencement of this project little was known about the likely mechanism of axonopathy in spartin HSP, indeed there was considerable disagreement in the literature as to its precise subcellular localisation. However, a putative role for spartin in endocytosis was proposed due to sequence homology identified with several proteins known to function in this area. This suggested that spartin belonged to an enlarging group of HSP proteins with membrane traffic and transport-related roles. This thesis had three primary aims: to clarify the subcellular localisation of endogenous spartin, to identify proteins that interacted with spartin, and to investigate a possible functional role(s) for spartin. Spartin was found to localise predominantly in the cytoplasm, with a cystosolic pool that was recruited to endosomes. Additionally, a proportion of spartin was found in mitochondria. Furthermore, spartin was shown to undergo multiple monoubiquitination and to interact with ubiquitin, two ankyrin repeat domain-13 family members, and also with the E3 ubiquitin ligase AIP4. Functional assays suggest that spartin is an inhibitor of epidermal growth factor receptor degradation, and negatively regulates bone morphogenetic protein (BMP) signalling. A putative role in BMP signalling is interesting because this pathway is emerging as an important regulator of distal axonal morphology and function, and has been implicated in the pathogenesis of another endosomal HSP protein, NIPA1. This suggests that altered BMP signalling may be a key pathological component of spartin HSP.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available