Intrinsic and Extrinsic Mechanisms Underlying Synaptic Proteostasis

2021 Scientific Innovations Award
Shigeki Watanabe, Ph.D.
Johns Hopkins University

Waste management and sustainability are major challenges humans face in the 21st-century. As you concentrate and think about these issues, nerve cells in your brain must deal with the exact same problem—how do they manage their trash? Unlike other cells in our body, most nurse cells must last our entire life and remain healthy enough to participate in an energy-consuming process: neuronal communication. Nerve cells communicate to each other at specialized contact points called synapses. During communication some cellular materials arerecycled at synapses and others are thrown away. The speed of this recycling and waste management is the key to sustaining neuronal communication and disrupting these processes can lead to neurodegenerative diseases. In fact, many risk factors for neurodegenerative disease have active products (i.e., proteins) that function at synapses and regulate how nerve cells handle their trash. It has been difficult to determine how these protein products normally function at synapses, how they are perturbed by disease-causing mutations and how their functions are assisted by the other support cells in the brain. This is partly because synapses are extremely small—only 1/500th the thickness of a hair—and many events related to neuronal communication occur extraordinarily fast—hundreds of times faster than the blink of an eye. Currently there is no way to observe such small structures and fast events at the same time.

Over the last few years, we have developed several techniques to overcome this hurdle, and we can observe events happening at synapses. One of the techniques, featured in our proposal, uses an electron microscope—a microscope that can visualize structures even hundreds of times smaller than synapses. To date, electron microscopy is the only method to clearly see all synapses and other cells interacting with these communication sites. However, it only captures static images of cells. To visualize ultrafast events at synapses, we induce neuronal communication and capture a series of snap-shots during the process to generate a “flipbook” of events occurring at the synapses. Using this approach, we can watch how neuron normally operates when communicating with another neuron. Our observations led to the new discovery of several ways materials are recycled and potentially degraded inside nerve cell synapses and how other brain cell types can help in this process. In this proposal, we will use our electron microscopy technique along with genetics, molecular biology, and biochemistry to deepen the understanding on how recycling and waste management works in the brain.

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