Open AccessElevated glucosylsphingosine in Gaucher disease induced pluripotent stem cell neurons deregulates lysosomal compartment through mammalian target of rapamycin complex 1
Author(s) -
Srikanth Manasa P.,
Jones Jace W.,
Kane Maureen,
Awad Ola,
Park Tea Soon,
Zambidis Elias T.,
Feldman Ricardo A.
Publication year - 2021
Publication title -
stem cells translational medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.781
H-Index - 71
eISSN - 2157-6580
pISSN - 2157-6564
DOI - 10.1002/sctm.20-0386
Subject(s) - autophagy , mtorc1 , pi3k/akt/mtor pathway , glucocerebrosidase , biology , mtorc2 , mechanistic target of rapamycin , lysosomal storage disease , microbiology and biotechnology , lysosome , induced pluripotent stem cell , neurodegeneration , lafora disease , biochemistry , signal transduction , phosphorylation , medicine , enzyme , apoptosis , disease , embryonic stem cell , gene , phosphatase
Gaucher disease (GD) is a lysosomal storage disorder caused by mutations in GBA1 , the gene that encodes lysosomal β‐glucocerebrosidase (GCase). Mild mutations in GBA1 cause type 1 non‐neuronopathic GD, whereas severe mutations cause types 2 and 3 neuronopathic GD (nGD). GCase deficiency results in the accumulation of glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph). GlcSph is formed by deacylation of GlcCer by the lysosomal enzyme acid ceramidase. Brains from patients with nGD have high levels of GlcSph, a lipid believed to play an important role in nGD, but the mechanisms involved remain unclear. To identify these mechanisms, we used human induced pluripotent stem cell‐derived neurons from nGD patients. We found that elevated levels of GlcSph activate mammalian target of rapamycin (mTOR) complex 1 (mTORC1), interfering with lysosomal biogenesis and autophagy, which were restored by incubation of nGD neurons with mTOR inhibitors. We also found that inhibition of acid ceramidase prevented both, mTOR hyperactivity and lysosomal dysfunction, suggesting that these alterations were caused by GlcSph accumulation in the mutant neurons. To directly determine whether GlcSph can cause mTOR hyperactivation, we incubated wild‐type neurons with exogenous GlcSph. Remarkably, GlcSph treatment recapitulated the mTOR hyperactivation and lysosomal abnormalities in mutant neurons, which were prevented by coincubation of GlcSph with mTOR inhibitors. We conclude that elevated GlcSph activates an mTORC1‐dependent pathogenic mechanism that is responsible for the lysosomal abnormalities of nGD neurons. We also identify acid ceramidase as essential to the pathogenesis of nGD, providing a new therapeutic target for treating GBA1 ‐associated neurodegeneration.