A role for p53 in the regulation of lysosomal permeability by Δ9-tetrahydrocannabinol in rat cortical neurones

Implications for neurodegeneration

Aoife Gowran, Veronica A. Campbell

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

The psychoactive ingredient of marijuana, Δ9- tetrahydrocannabinol (Δ9-THC), can evoke apoptosis in cultured cortical neurones. Whilst the intracellular mechanisms responsible for this apoptotic pathway remain to be fully elucidated, we have recently identified a role for the CB1 type of cannabinoid (CB) receptor and the tumour suppressor protein, p53. In the current study, we demonstrate the Δ9-THC promotes a significant increase in lysosomal permeability in a dose- and time-dependent manner. The increase in lysosomal permeability was blocked by the CB1 receptor antagonist, AM251. Δ9-THC increased the localization of phospho-p53Ser15 at the lysosome and stimulated the release of the lysosomal cathepsin enzyme, cathepsin-D, into the cytosol. The p53 inhibitor, pifithrin-α and small interfering RNA-mediated knockdown of p53 prevented the Δ9-THC- mediated increase in lysosomal permeability. Furthermore, the Δ9-THC -mediated induction of apoptosis was abrogated by a cell-permeable cathepsin-D inhibitor (10 μM). Thus, the study demonstrates that Δ9-THC impacts on the lysosomal system, via p53, to evoke lysosomal instability as an early event in the apoptotic cascade. This provides evidence for a novel link between the CB1 receptor and the lysosomal branch of the apoptotic pathway which is crucial in regulating neuronal viability following exposure to Δ9-THC.

Original languageEnglish
Pages (from-to)1513-1524
Number of pages12
JournalJournal of Neurochemistry
Volume105
Issue number4
DOIs
Publication statusPublished - May 2008

Fingerprint

Dronabinol
Neurons
Rats
Permeability
Cannabinoid Receptor CB1
Cathepsin D
Apoptosis
Tumor Suppressor Protein p53
Cathepsins
Cannabis
Lysosomes
Cytosol
Small Interfering RNA
Enzymes

Keywords

  • Δ-tetrahydrocannabinol
  • Apoptosis
  • Lysosomes
  • Neuron
  • p53

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

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title = "A role for p53 in the regulation of lysosomal permeability by Δ9-tetrahydrocannabinol in rat cortical neurones: Implications for neurodegeneration",
abstract = "The psychoactive ingredient of marijuana, Δ9- tetrahydrocannabinol (Δ9-THC), can evoke apoptosis in cultured cortical neurones. Whilst the intracellular mechanisms responsible for this apoptotic pathway remain to be fully elucidated, we have recently identified a role for the CB1 type of cannabinoid (CB) receptor and the tumour suppressor protein, p53. In the current study, we demonstrate the Δ9-THC promotes a significant increase in lysosomal permeability in a dose- and time-dependent manner. The increase in lysosomal permeability was blocked by the CB1 receptor antagonist, AM251. Δ9-THC increased the localization of phospho-p53Ser15 at the lysosome and stimulated the release of the lysosomal cathepsin enzyme, cathepsin-D, into the cytosol. The p53 inhibitor, pifithrin-α and small interfering RNA-mediated knockdown of p53 prevented the Δ9-THC- mediated increase in lysosomal permeability. Furthermore, the Δ9-THC -mediated induction of apoptosis was abrogated by a cell-permeable cathepsin-D inhibitor (10 μM). Thus, the study demonstrates that Δ9-THC impacts on the lysosomal system, via p53, to evoke lysosomal instability as an early event in the apoptotic cascade. This provides evidence for a novel link between the CB1 receptor and the lysosomal branch of the apoptotic pathway which is crucial in regulating neuronal viability following exposure to Δ9-THC.",
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