Axonal transport of lysosomes in glucocerebrosidase-deficient iPSC-derived neurons

Thesis type
(Thesis) M.Sc.
Date created
2022-01-12
Authors/Contributors
Abstract
Lysosomes are acidic organelles that traffic throughout neurons delivering catabolic enzymes to distal regions of the cell and maintaining degradative demands. Loss of function mutations in the lysosomal enzyme glucocerebrosidase (GBA) cause the lysosomal storage disorder Gaucher's Disease and are a risk factor for synucleinopathies like Parkinson's Disease and Dementia with Lewy Bodies. GBA degrades the membrane lipid glucosylceramide, but mutations in GBA, or its catalytic inhibition, cause the accumulation of glucosylceramide and disturb the composition of the lysosomal membrane. Because the lysosomal membrane serves as the platform to which intracellular trafficking complexes are recruited and activated, I investigated if inhibition of GCase activity with Conduritol B Epoxide (CBE) interfered with lysosomal trafficking in axons. In human iPSC-derived neurons treated with CBE, lysosomal transport dynamics, lysosomal rupture, and exocytosis, were unaffected. These results suggest the loss of GCase activity does not contribute to neurodegenerative disease by disrupting these lysosomal processes.
Document
Identifier
etd21780
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Supervisor or Senior Supervisor
Thesis advisor: Silverman, Michael
Language
English
Member of collection
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