ORCID Profile
0000-0003-4521-7978
Current Organisation
Universidad San Sebastián - Campus Bellavista
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Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.BBADIS.2016.08.016
Abstract: Niemann-Pick type C (NPC) disease is characterized by lysosomal accumulation of cholesterol. Interestingly, NPC patients' brains also show increased levels of amyloid-β (Aβ) peptide, a key protein in Alzheimer's disease pathogenesis. We previously reported that the c-Abl tyrosine kinase is active in NPC neurons and in AD animal models and that Imatinib, a specific c-Abl inhibitor, decreased the amyloid burden in brains of the AD mouse model. Active c-Abl was shown to interact with the APP cytosolic domain, but the relevance of this interaction to APP processing has yet to be defined. In this work we show that c-Abl inhibition reduces APP amyloidogenic cleavage in NPC cells overexpressing APP. Indeed, we found that levels of the Aβ oligomers and the carboxy-terminal fragment βCTF were decreased when the cells were treated with Imatinib and upon shRNA-mediated c-Abl knockdown. Moreover, Imatinib decreased APP amyloidogenic processing in the brain of an NPC mouse model. In addition, we found decreased levels of βCTF in neuronal cultures from c-Abl null mice. We demonstrate that c-Abl directly interacts with APP, that c-Abl inhibition prevents this interaction, and that Tyr682 in the APP cytoplasmic tail is essential for this interaction. More importantly, we found that c-Abl inhibition by Imatinib significantly inhibits the interaction between APP and BACE1. We conclude that c-Abl activity facilitates the APP-BACE1 interaction, thereby promoting amyloidogenic processing of APP. Thus, inhibition of c-Abl could be a pharmacological target for preventing the injurious effects of increased Aβ levels in NPC disease.
Publisher: American Society for Cell Biology (ASCB)
Date: 09-2007
Abstract: The sorting of acid hydrolase precursors at the trans-Golgi network (TGN) is mediated by binding to mannose 6-phosphate receptors (MPRs) and subsequent capture of the hydrolase-MPR complexes into clathrin-coated vesicles or transport carriers (TCs) destined for delivery to endosomes. This capture depends on the function of three monomeric clathrin adaptors named GGAs. The GGAs comprise a C-terminal “ear” domain that binds a specific set of accessory proteins. Herein we show that one of these accessory proteins, p56, colocalizes and physically interacts with the three GGAs at the TGN. Moreover, overexpression of the GGAs enhances the association of p56 with the TGN, and RNA interference (RNAi)-mediated depletion of the GGAs decreases the TGN association and total levels of p56. RNAi-mediated depletion of p56 or the GGAs causes various degrees of missorting of the precursor of the acid hydrolase, cathepsin D. In the case of p56 depletion, this missorting correlates with decreased mobility of GGA-containing TCs. Transfection with an RNAi-resistant p56 construct, but not with a p56 construct lacking the GGA-ear–interacting motif, restores the mobility of the TCs. We conclude that p56 tightly cooperates with the GGAs in the sorting of cathepsin D to lysosomes, probably by enabling the movement of GGA-containing TCs.
No related grants have been discovered for Patricia V. Burgos Hitschfeld.