Yuliang Wang, United States of America
University of Washington Computer Science and EngineeringAuthor Of 1 Presentation
THE AD RISK GENE SORL1 REGULATES ENDOCYTIC TRAFFICKING OF NEURONAL CARGO IN HIPSC-DERIVED NEURONS
Abstract
Aims
The sorting receptor SorLA is encoded by the well-established Alzheimer’s disease risk gene SORL1. SorLA is established as a sorting receptor that mediates endosome to Golgi trafficking of the amyloid precursor protein. Loss of SORL1 impedes retrograde trafficking of APP, leads to early endosome traffic jams and increases processing of APP to amyloid beta. We have recently shown that loss of SORL1 leads to early endosome enlargement, an established AD cytopathology. Our objective in this study is to further explore endo-lysosomal trafficking impairments in neurons that lead to neurodegeneration.
Methods
We used isogenic hiPSC-derived neurons deficient in or with enhanced SORL1 expression and examined endocytic cargo trafficking, lysosomal degradation, neuronal functional activity, and transcriptomic responses to loss of SORL1.
Results
We find that loss of SORL1 impairs trafficking of multiple cargo including the neurotrophin receptor TrkB and the Glutamate receptor GLUR1. Functionally, loss of SORL1 impedes lysosomal degradation and impacts neuronal synaptic function. RNA-sequencing analyses shows altered network interaction changes in neurotrophin and synaptic genes, demonstrating that endosomal traffic jams induced by loss of SorLA expression lead to impairment of pathways that are necessary for neuronal health and function. Finally, we demonstrate both genetically and pharmacologically that enhanced SORL1 expression and small molecules that enhance endosomal trafficking promote cargo trafficking and rescue endosome enlargement induced by SORL1 deficiency in neurons.
Conclusions
Collectively our data suggests that SORLA plays multiple roles in neuronal endo-lysosomal trafficking that impact health and function of neurons. Furthermore, strategies enhancing endosomal trafficking should be considered as therapeutic targets for AD.