ABL inhibition activates TFEB and promotes cellular clearance in the lysosomal storage disorder Niemann-pick type C. ; LA INHIBICIÓN DE LA QUINASA ABL ACTIVA AL FACTOR TFEB Y PROMUEVE LA LIMPIEZA CELULAR EN LA ENFERMEDAD LISOSOMAL DE NIEMANN-PICK C
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E-Book
Title:
ABL inhibition activates TFEB and promotes cellular clearance in the lysosomal storage disorder Niemann-pick type C. ; LA INHIBICIÓN DE LA QUINASA ABL ACTIVA AL FACTOR TFEB Y PROMUEVE LA LIMPIEZA CELULAR EN LA ENFERMEDAD LISOSOMAL DE NIEMANN-PICK C
imprint:
[Erscheinungsort nicht ermittelbar]: [Verlag nicht ermittelbar], 20XX
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Not determined
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Origination:
University thesis:
Dissertation
Footnote:
Description:
Lysosomes are cellular organelles that play a fundamental role in cellular homeostasis because they are involved in different process such as: membrane repair, degradation and recycling of nutrients, macromolecules metabolism and autophagy. Deficiencies in lysosomal proteins promote the accumulation of different molecules in the organelle causing multiples lysosomal diseases, such as Niemann-Pick type C (NPC), which is characterized by lysosomal cholesterol accumulation due to mutations in the genes encoding for the NPC1 and NPC2 proteins. Interestingly, in the last time the transcription factor EB (TFEB) has been described as the master regulator of lysosomal biogenesis and gene expression related to autophagy. The activity and nuclear translocation of TFEB depends on its phosphorylation status in serine 211 and 142, which are regulated by the serine/threonine kinase mTORC1. At basal conditions, TFEB is phosphorylated in these serines and is retained in the cytoplasm due to its attachment to the cytosolic chaperone 14-3-3. Previously, our lab described that the tyrosine kinase ABL is activated in NPC disease. The Inhibition of this kinase using Imatinib, an ABL specific inhibitor, prevents the neuronal death in the cerebellum and improves the locomotor function and survival of the NPC mice. In addition, it has been described that the use of pharmacological ABL inhibitors induces the autophagy flux and an increase in the lysosomal levels. Nevertheless, the cellular mechanism by which ABL inhibition induces these changes are still unknown. Considering this data, the hypothesis of this thesis is the following: ABL signaling promotes TFEB cytoplasmic localization, inhibiting cellular clearance and contributing to the pathogenesis of the lysosomal storage disease Niemann-Pick type C". To test our hypothesis, first we evaluated TFEB nuclear translocation by the high-content screening technique, using different ABL inhibitors. We found that ABL inhibition by these inhibitors promotes TFEB nuclear translocation. The same results were obtained analyzing nuclear-cytoplasmic fractions, as well as evaluating endogenous TFEB cellular localization. In addition, we observed the same results