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Induced Pluripotent Stem Cell-derived Neurons Provide Mechanistic Insight into Lysosomal Storage Disorder

Review of "Elevated glucosylsphingosine in Gaucher disease induced pluripotent stem cell neurons deregulates lysosomal compartment through mammalian target of rapamycin complex 1" from STEM CELLS Translational Medicine by Stuart P. Atkinson

Severe mutations in GBA1, which encodes the lysosomal β‐glucocerebrosidase enzyme, prompt the massive accumulation of neurotoxic glucosphingolipids such as glucosylceramide and glucosylsphingosine in the central nervous system, which induce the onset of a lysosomal storage disorder known as neuronopathic Gaucher disease (nGD) [1-4]. Previous research led by Ricardo A. Feldman (University of Maryland School of Medicine, Baltimore, MD, USA) established that the hyperactivity of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1), a nutrient and energy sensor that regulates the fine balance between anabolism and catabolism, in nGD neurons deregulates the autophagy lysosomal pathway [5].

In their most recent STEM CELLS Translational Medicine article [6], Srikanth et al. now report on their exploration of the links between glucosphingolipid accumulation and mTORC1 activity in human induced pluripotent stem cell‐derived neurons from nGD patients in the hope of uncovering new therapeutic targets.

The authors discovered that the elevated levels of glucosylsphingosine in nGD neurons activated mTORC1, which interfered with normal lysosomal biogenesis and blocked autophagy. While the exposure of nGD neurons to an mTOR inhibitor reversed the effects of glucosylsphingosine accumulation, the inhibition of the lysosomal enzyme acid ceramidase (which catalyzes the deacylation of glucosylceramide, the last step in glucosylsphingosine formation) also prevented mTORC1 hyperactivity and lysosomal dysfunction and restored autophagic flux, highlighting the induction of disease-associated alterations with GlcSph accumulation in the mutant neurons (See image - Acid ceramidase inhibition in GD2 neurons reduces mTOR hyperactivity and rescues lysosomal biogenesis). Furthermore, the incubation of wild‐type neurons with exogenous glucosylsphingosine prompted mTORC1 hyperactivation and the onset of abnormalities in lysosomal biogenesis and autophagic flux observed in nGD neurons, while the addition of mTOR inhibitors blocked any effects of glucosylsphingosine exposure.

Overall, the results of this exciting human induced pluripotent stem cell-based study provide robust evidence for a mechanistic link between elevated glucosylsphingosine levels, mTORC1 hyperactivation, and lysosomal dysfunction, but also identify acid ceramidase and the formation of glucosylsphingosine from glucosylceramide as a new target for the development of nGD specific therapeutics. Additionally, these findings support a role for the mTORC1 as a vital sensor of sphingolipid imbalance.

For more on how human induced pluripotent stem cells can provide mechanistic insight into lysosomal storage disorders, stay tuned to the Stem Cells Portal!


References

  1. Farfel-Becker T, Vitner EB, Kelly SL, et al., Neuronal accumulation of glucosylceramide in a mouse model of neuronopathic Gaucher disease leads to neurodegeneration. Human Molecular Genetics 2014;23:843-854.
  2. Nilsson O and Svennerholm L, Accumulation of Glucosylceramide and Glucosylsphingosine (Psychosine) in Cerebrum and Cerebellum in Infantile and Juvenile Gaucher Disease. Journal of Neurochemistry 1982;39:709-718.
  3. Hallett PJ, Huebecker M, Brekk OR, et al., Glycosphingolipid levels and glucocerebrosidase activity are altered in normal aging of the mouse brain. Neurobiology of Aging 2018;67:189-200.
  4. Orvisky E, Sidransky E, McKinney CE, et al., Glucosylsphingosine Accumulation in Mice and Patients with Type 2 Gaucher Disease Begins Early in Gestation. Pediatric Research 2000;48:233-237.
  5. Brown RA, Voit A, Srikanth MP, et al., mTOR hyperactivity mediates lysosomal dysfunction in Gaucher's disease iPSC-neuronal cells. Disease Models & Mechanisms 2019;12.
  6. Srikanth MP, Jones JW, Kane M, et al., Elevated glucosylsphingosine in Gaucher disease induced pluripotent stem cell neurons deregulates lysosomal compartment through mammalian target of rapamycin complex 1. STEM CELLS Translational Medicine 2021;10:1081-1094.