Protein complexes and cholesterol in the control of late endosomal dynamics : Cholesterol and multi-protein complexes in the control of late endosomal dynamics

Late endosomal transport is disrupted in several diseases such as Niemann-Pick type C, ARC syndrome and Alzheimer__s disease. This thesis describes the regulation of late endosomal dynamics by cholesterol and multi-protein complexes. We find that cholesterol acts as a cellular tomtom that steers the direction of late endosomal transport by dynein-motors, and that this process is disrupted in Niemann-Pick disease. Furthermore cholesterol also regulates tethering via the multi-subunit HOPS complex. Homologues of this complex are mutated in ARC syndrome patients and the cellular consequences are described in this thesis. We find that the cholesterol sensing proteins ORP1L and MLN64 are major regulators of late endosomal transport, and that this transport is further regulated by the endoplasmatic reticulum.