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Publications of the Week

The Alzheimer’s Gene SORL1 Is a Regulator of Endosomal Traffic and Recycling in Human Neurons

By March 16, 2022March 21st, 2022No Comments

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This week we profile a recent publication in Cellular and Molecular Life Sciences from Dr. Swati Mishra (pictured, left), Allison Knupp (center), and the laboratory of Dr. Jessica Young (right) at the Institute for Stem Cell and Regenerative Medicine at UW.

Can you provide a brief overview of your lab’s current research focus?

Broadly, our lab aims to dissect cellular mechanisms that go awry in Alzheimer’s disease, the most common neurodegenerative disorder. To do this, we use human induced pluripotent stem cells which we differentiate to neurons and glial cells. One project in our lab focuses on how endo-lysosomal trafficking, a process that directs proteins in cells to the correct location or facilitates their degradation, may be impaired in AD. We think this is an important pathway to target for new therapeutic development.

What is the significance of the findings in this publication?

In this work, we continued our studies on the gene SORL1, which is emerging as a highly pathogenic AD risk gene. Loss of SORL1 expression appears to be a causative event for the development of AD. Our previous study (Knupp et al., Cell Reports 2020) showed that loss of SORL1 in neurons leads to dysfunction in the endosomal network. In our current work, we mapped the trafficking path of key proteins important for neuronal function in cells deficient for SORL1. In particular, we looked at the trafficking of neurotrophin receptors and glutamate receptors, both proteins that are essential for healthy neuronal function and synapse development. In SORL1 deficient cells we saw aberrant trafficking of these proteins, they were stuck in endosomal vesicles rather than getting to their correct localization. We think that this may represent a very early dysfunction that contributes to neurodegeneration. Interestingly when we looked at neurons with enhanced SORL1 expression, we saw that the trafficking of these proteins was improved. This is exciting because it points towards this pathway for potential therapeutic development.

What are the next steps for this research?

There are several next steps that we are pursuing. First, we want to further define how aberrant endo-lysosomal trafficking affects neuronal synaptic function. This is important as the loss of synapses is the first step toward neurodegeneration. Second, we want to understand how altered trafficking impacts other brain cells such as glia. Each cell type of the brain utilizes this pathway in a unique way and may be differentially impacted in the disease state and by potential therapies. Using our hiPSC model, we can dissect this pathway in a cell-type-specific manner. Finally, we want to test novel small molecules that may target the endo-lysosomal network to see if phenotypes that we observe can be ameliorated. We believe that these types of experiments will be essential in new therapy development for AD.

If you’d like us to mention your funding sources, please list them.

This project was funded by generous grants from the BrightFocus Foundation, the National Institute on Aging, and a philanthropic gift to UW.  

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