mTOR hyperactivity mediates lysosomal dysfunction in Gaucher's disease iPSC-neuronal cells

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Bi-allelic GBA1 mutations cause Gaucher's disease (GD), a lysosomal storage disorder with severe neurodegeneration.
• GBA1 mutations are a major genetic risk factor for Parkinson's disease (PD).
• Autophagy-lysosomal pathway dysfunction is a key mechanism in GBA1-associated neurodegeneration.

Purpose of the Study:

• To investigate the mechanism of autophagy-lysosomal pathway dysfunction in neuronopathic GD.
• To examine the role of mammalian target of rapamycin complex 1 (mTORC1) kinase activity in GD.
• To explore the therapeutic potential of targeting mTORC1 in GBA1-associated neurodegeneration.

Main Methods:

• Utilized an induced pluripotent stem cell (iPSC) model of GD.
• Assessed mTORC1 kinase activity in GD iPSC-derived neuronal progenitors and neurons.
• Investigated the effect of pharmacological inhibition of glucosylceramide synthase and mTORC1 (Torin1).

Main Results:

• mTORC1 was found to be hyperactive in GD cells, indicated by increased phosphorylation of its substrates.
• Inhibition of glucosylceramide synthase reversed mTORC1 hyperactivation, suggesting glycosphingolipid accumulation mediates this.
• mTORC1 inhibition (Torin1) restored lysosomal biogenesis and autophagic clearance in GD neurons.
• Increased mTORC1 activity led to higher TFEB phosphorylation and decreased TFEB stability in GD cells.

Conclusions:

• The study uncovers a novel mechanism of autophagy-lysosomal pathway dysfunction in GD.
• Hyperactive mTORC1 signaling, driven by glycosphingolipid accumulation, contributes to neurodegeneration in GD.
• The mTOR complex represents a potential therapeutic target for GBA1-associated neurodegeneration.