Regulatory Mechanisms Underlying Endosomal Targeting of SORL1

The goal is to identify novel mechanisms that regulate sorting of SORL1 to and from the endo-lysosomal network.

The sorting of SORL1 in compartments of the endolysosomal network strongly depends on binding of its short tail-domain to trafficking proteins in the cytosol. Our aim is to identify novel binding partners and to uncover how their interactions with SORL1 is regulated by post-translational modifications, including kinase activity that modify specific parts of the SORL1 tail.

Current knowledge on the intracellular trafficking itinerary of SORL1 is limited to studies from common cell lines, and only few details on its sorting steps in human neurons. Here we want to expand our knowledge focusing also on SORL1 binding partners and sorting steps in neurons as well as starting to address its trafficking pathway also in glia cells, including how on/off-signals can be regulated by phosphorylation of key residues within SORL1 sorting signals.

As SORL1 is a major contributing factor for familial Alzheimer’s disease, an improved understanding of its biology related to disease mechanisms holds the promise for a better understanding of disease etiology for patients suffering from defects in the SORL1-trafficking pathway. This can potentially open for novel therapeutic strategies of benefits for the public.