Use this URL to cite or link to this record in EThOS:
Title: Connecting Ca2+ stores and Parkinson disease
Author: Kilpatrick, B. S.
ISNI:       0000 0004 5365 0322
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2015
Availability of Full Text:
Access from EThOS:
Full text unavailable from EThOS. Please try the link below.
Access from Institution:
Accumulating evidence implicates lysosomes as mobilisable stores of Ca2+, but their relationship to the better-characterised endoplasmic reticulum (ER) Ca2+ store and significance for disease remains unclear. Here I show that the rapid osmotic permeabilisation of lysosomes evokes prolonged, spatiotemporally complex Ca2+ signals in primary cultured human fibroblasts. These Ca2+ signals comprised an initial response that correlated with lysosomal disruption and secondary long-lasting spatially heterogeneous Ca2+ oscillations that required ER-localised inositol trisphosphate receptors. Pharmacological and molecular inhibition of the trafficking protein Rab7 supressed lysosome induced Ca2+ oscillations. A synthetic agonist, of the endolysosomal ion channel TRPML, also evoked ER-dependent complex Ca2+ signals. Thus, like the Ca2+ messenger NAADP, direct mobilisation of lysosomal Ca2+ stores is sufficient to evoke ER-dependent Ca2+ signals through a mechanism that maybe Rab7-dependent. I also identify Ca2+ defects in fibroblasts from Gaucher disease (GD) and Parkinson disease (PD) patients with mutations in the gene (GBA1) encoding the lysosomal enzyme glucocerebrosidase. ER Ca2+ levels were increased in younger (but not older) patients and associated with enhanced responses to the ryanodine receptor modulator, cyclic ADP-ribose. ER Ca2+ signalling was unaffected by molecular or chemical inhibition of glucocerebrosidase, implicating mis-folded enzyme in pathology. Conversely, lysosomal Ca2+ signals were reduced in GD and PD and associated with disrupted lysosome morphology. Therefore, remodelling of ER-lysosomal Ca2+ stores by pathogenic GBA1 might predispose to PD. Finally, I identify lysosomal morphology defects in fibroblasts from PD patients with a common mutation in the enzyme LRRK2. These defects were reversed by silencing the endolysosomal ion channel, TPC2. Lysosomal pathology was recapitulated in SH-SY5Y cells overexpressing mutant LRRK2 and by an environmental toxin linked to PD. Ca2+ dependent regulation of lysosomal morphology may thus contribute in PD pathology. In summary, Ca2+ stores are functionally connected and their compromised homeostasis might connect to PD pathology.
Supervisor: Patel, S. ; Schapira, A. H. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available