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Title: Lysosomal storage disorders and neurodegenerative disease : related mechanisms of pathogenesis and identification of novel therapeutic targets
Author: Haslett, Luke
ISNI:       0000 0004 5917 7302
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2015
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Lysosomal storage disorders (LSDs) are rare diseases caused by inherited mutations in genes coding for proteins of the endolysosomal system. The lysosome is an organelle responsible for the degradation of dysfunctional organelles and for the catabolism, and subsequent recycling, of macromolecules within the cell. When this process becomes defective the substrates of lysosomal catabolism accumulate; these can include lipids, proteins, polysaccharides, nucleotides and diverse combinations of all three. The phenotypic spectrum of these diseases in isolation, and even more so as a group, is extremely broad but an almost universal consequence of lysosomal dysfunction is severe, early onset neurodegeneration. Neurodegenerative diseases of ageing such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease represent a major challenge to the provision of human healthcare in light of an ageing global population. Whilst some commonalities exist between these three diseases a myriad of hypotheses for the onset of pathology has been proposed. There is growing evidence for involvement of the lysosome in all three of these diseases. We have been looking at specific lysosomal pathologies such as lipid storage, endocytosis and Ca2+ dysregulation in forms of these three neurodegenerative diseases of ageing whilst using LSDs as models to inform our study. We have found that lysosomal alkalisation in familial models of Alzheimer’s disease results in changes to lipid and Ca2+ homeostasis in this compartment and identified a lysosomal ion channel, transient receptor potential cation channel, mucolipin subfamily, member 1 (TRPML1), as a key constituent of this process. Our study of models of Huntington’s disease have implicated the Niemann-Pick type C1 protein (NPC1) in the pathogenesis of this disease and identified ways in which this could be therapeutically targeted. Finally, we have found evidence of Ca2+ dyshomeostasis throughout the cell in genetic models of Parkinson’s disease which have defects in lysosomal proteins. Taken together, these studies strengthen the evidence for lysosomal involvement in neurodegenerative diseases of ageing, albeit with different mechanisms in each case, whilst expanding on the molecular basis for these processes. Accordingly, our understanding of the mechanisms underlying the pathogenesis of these diseases has improved and new therapeutic targets have been identified by these studies.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QH301 Biology ; RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry