Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.769894
Title: Endoplasmic reticulum-mitochondria associations and amyotrophic lateral sclerosis
Author: Stoica, Radu
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2013
Availability of Full Text:
Access from EThOS:
Access from Institution:
Abstract:
Damage to both mitochondria and the endoplasmic reticulum (ER) involving ER stress and the unfolded protein response (UPR) are characteristic features in amyotrophic lateral sclerosis (ALS). However, how these two pathological features might be linked in a common disease pathway is unclear. Approximately 5-20% of the mitochondrial surface is closely apposed to ER and tethers linking the two organelles can be visualised via electron microscopy. These regions mediate a number of physiological processes including Ca2+ and phospholipid exchange between ER and mitochondria, ER and mitochondrial stress responses and apoptosis. Moreover, defects in ER-mitochondria associations are now known to contribute to neurodegenerative diseases. To properly investigate the role of ER-mitochondria associations in physiological processes and disease situations, the identity of the molecular tethers that physically link ER with mitochondria needs to be established. Previous work from our research group identified the outer mitochondrial membrane protein, protein tyrosine phosphatase-interacting protein 51 (PTPIP51) as a binding partner for the resident ER protein vesicle-associated membrane protein-associated protein-B (VAPB). As such, VAPB and PTPIP51 represent plausible candidates for mediating ER-mitochondria associations. In order to test this possibility, ER and mitochondria associations were quantified following the experimental manipulation of VAPB and/or PTPIP51 expression. The results strongly support a role for VAPB and PTPIP51 in controlling ER-mitochondria associations. TAR DNA-binding protein-43 (TDP-43) is strongly linked to ALS and mutations in TARDBP, the gene encoding TDP-43, are the cause of some familial forms of the disease. The effects of TDP-43 expression on ER-mitochondria associations and binding of VAPB to PTPIP51 were investigated. The results showed that both wild-type and ALS mutant TDP-43 disrupt ER-mitochondria associations and that this is accompanied by decreased binding of VAPB to PTPIP51. Mutations in the genes encoding fused in sarcoma (FUS) and Cu/Zn superoxide dismutase-1 (SOD1) also cause some familial forms of ALS and preliminary investigations revealed that FUS but not SOD1 also decreases VAPB-PTPIP51 interactions. Finally, the mechanisms that regulate binding of VAPB to PTPIP51 were investigated. Phosphorylation is known to influence protein-protein interactions and phosphorylation sites in VAPB and PTPIP51 were identified by mass spectrometry. However, mutation of these sites did not influence VAPB-PTPIP51 binding.
Supervisor: Miller, Christopher Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.769894  DOI: Not available
Share: