3D artistic representation of three human neurons. The neuron bodies are slightly translucent, showing a hint of the organelles within. Two of the background neurons fade into the distance. The foreground neuron has a small keyhole inset over its body, revealing the interior structures of the cell – namely the Trans-Golgi network and various endosomes and lysosomes.3D artistic representation of three human neurons. The neuron bodies are slightly translucent, showing a hint of the organelles within. Two of the background neurons fade into the distance. The foreground neuron has a small keyhole inset over its body, revealing the interior structures of the cell – namely the Trans-Golgi network and various endosomes and lysosomes.

Our Science

The endolysosome transports critical proteins within the cell. It is an essential system of human cell biology. On the molecular level, it is regulated by the retromer complex. Disruption of key retromer complex proteins contributes to neurodegenerative disease.

The endolysosome is the cell's protein processing system.

The endolysosomal system comprises a series of interconnected waypoints within cells. Efficient molecular movement through these waypoints is important for maintaining cellular health. Particularly vital for healthy neuronal function, endolysosomal trafficking regulates how well neurons communicate with each other—a primary function of the brain—and is required to dispose of materials that are toxic to neurons.

Overview of the endolysosomal system. In the upper left-hand side, there is a 3D neuron from which extends out a leader line to an inset that takes up the rest of the visual. In the inset is a 3D cross-section showing the interior of a portion of the cell body. In the cell membrane are a number of surface proteins that are taken into the cell and processed through an early endosome. Parts of the early endosome membrane extend out and form tubules to ferry proteins where they need to go. These tubules get covered in the retromer complex, which allows them to break off the endosome and traffic to other parts of the cell, like the Trans-Golgi network through the retrograde pathway, to the late endosome/lysosome through the degradation pathway, and back into the cell membrane through the recycling pathway.Overview of the endolysosomal system. In the upper left-hand side, there is a 3D neuron from which extends out a leader line to an inset that takes up the rest of the visual. In the inset is a 3D cross-section showing the interior of a portion of the cell body. In the cell membrane are a number of surface proteins that are taken into the cell and processed through an early endosome. Parts of the early endosome membrane extend out and form tubules to ferry proteins where they need to go. These tubules get covered in the retromer complex, which allows them to break off the endosome and traffic to other parts of the cell, like the Trans-Golgi network through the retrograde pathway, to the late endosome/lysosome through the degradation pathway, and back into the cell membrane through the recycling pathway.

Traffic through the endolysosome is highly dynamic.

The endolysosomal system maintains myriad cellular functions through dynamic sorting and transport of protein cargo. In the degradation pathway, proteins and lipids move from compartments called “endosomes” to the lysosome, where they are broken down. In contrast, the recycling pathway moves proteins and lipids from the endosome back to the cell surface, while the retrograde pathway shuttles them between the endosome and the Golgi apparatus.
 
 

The retromer complex is the master regulator of endolysosomal transport.

Retromer—a large protein complex—regulates the movement of proteins through the endolysosomal system. The retromer complex comprises multiple subunits, which interact and work together to transport cargo. The components of the retromer complex include a cargo receptor and a trimeric core.

How the retromer complex transports cargo

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A transmembrane cargo receptor protein recognizes a cargo protein inside the endosomal compartment. One such receptor is SORL1, which is critical for retromer complex function.
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The three-subunit core of the retromer complex interacts with the cargo receptor.
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Many complexes assemble into a scaffold that stabilizes an extension of the compartment.
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Inside the cell, the trimeric core interacts with cytoskeleton proteins that move the compartment—with its cargo inside—to the correct location.
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A transmembrane cargo receptor protein recognizes a cargo protein inside the endosomal compartment. One such receptor is SORL1, which is critical for retromer complex function.

Disruption of the endolysosomal system has been shown to contribute to neurodegenerative disease.

For some individuals living with diseases like Alzheimer’s and Parkinson’s, genetic variants corresponding to critical proteins of the retromer complex—including SORL1 and the trimeric core—have been causally linked to disease onset. Defects in the retromer pathway trigger these diseases by disrupting the endolysosomal system.

Endolysosomal disruption is a triggering event for other neurodegenerative diseases like ALS and tauopathies. While retromer proteins might not be primarily defective in these diseases, retromer enhancement can also remediate the causal mechanisms.

With strategies informed by human genetics, we are designing therapies to enhance molecular transport through the endolysosomal system.

 
 

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