Axonal Transport of Lysosomes Is Unaffected in Glucocerebrosidase-Inhibited iPSC-Derived Forebrain Neurons

eNeuro · 5 authors, 4 centres

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TL;DR

This study used live cell imaging of human iPSC-derived forebrain neurons to test if inhibiting the enzyme GCase with CBE disrupts lysosomal transport or rupture. The central result was that axonal lysosomal transport and susceptibility to rupture were not significantly altered by GCase inhibition.

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The study investigated whether inhibiting the lysosomal enzyme glucocerebrosidase (GCase) with Conduritol B Epoxide (CBE) in human iPSC-derived forebrain neurons alters axonal lysosomal trafficking or rupture. Using live-cell imaging and immunocytochemistry, researchers compared lysosomal transport dynamics and rupture susceptibility between control and CBE-treated neurons. The results showed no significant difference in the anterograde or retrograde transport of lysosomes between the two conditions. Similarly, when lysosomal rupture was induced with L-leucyl-L-leucine methyl ester (LLoME), there was no significant difference in susceptibility between control and CBE-treated neurons. The authors conclude that GCase inhibition via this specific CBE treatment regimen does not disrupt these two lysosomal processes, suggesting a loss of GCase activity may not directly contribute to neurodegenerative disease through these mechanisms in this model. Limitations include the use of a specific pharmacological inhibition method and the potential that longer treatment durations or more complex disease models might be needed to observe effects.

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other

SPECIALTY

neurology

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ORIGINAL PAPER

PMC10576257

Axonal Transport of Lysosomes Is Unaffected in Glucocerebrosidase-Inhibited iPSC-Derived Forebrain Neurons

eNeuro

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ABSTRACT

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 gene GBA encoding the lysosomal enzyme glucocerebrosidase (GCase) cause the lysosomal storage disorder Gaucher’s disease (GD) and are the most common genetic risk factor for synucleinopathies like Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). GCase degrades the membrane lipid glucosylceramide (GlcCer) and mutations in GBA , or inhibiting its activity, results in the accumulation of GlcCer and disturbs the composition of the lysosomal membrane. The lysosomal membrane serves as the platform to which intracellular trafficking complexes are recruited and activated. Here, we investigated whether lysosomal trafficking in axons was altered by inhibition of GCase with the pharmacological agent Conduritol B Epoxide (CBE). Using live cell imaging in human male induced pluripotent human stem cell (iPSC)-derived forebrain neurons, we demonstrated that lysosomal transport was similar in both control and CBE-treated neurons. Furthermore, we tested whether lysosomal rupture, a process implicated in various neurodegenerative disorders, was affected by inhibition of GCase. Using L-leucyl-L-leucine methyl ester (LLoME) to induce lysosomal membrane damage and immunocytochemical staining for markers of lysosomal rupture, we found no difference in susceptibility to rupture between control and CBE-treated neurons. These results suggest the loss of GCase activity does not contribute to neurodegenerative disease by disrupting either lysosomal transport or rupture.

CITATION EXPORT

A. J. Keefe, D. R. Gabrych, Y. Zhu et al.. Axonal Transport of Lysosomes Is Unaffected in Glucocerebrosidase-Inhibited iPSC-Derived Forebrain Neurons. eNeuro. (2023). https://doi.org/10.1523/ENEURO.0079-23.2023

AUTHORS

5 · 4 CENTRES

A. J. Keefe, D. R. Gabrych, Y. Zhu, D. J. Vocadlo, M. A. Silverman

1Department of Biological Sciences, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada
2Centre for Cell Biology, Development, and Disease, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada
3Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada
4Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada