Revolutionizing Nerve Repair: Scientists Discover Key Protein in Mice

Innovating Nerve Restoration: Scientists Uncover Vital Protein in Mice

Researchers at the Salk Institute have made a groundbreaking discovery in the field of peripheral neuropathy, shedding light on the critical role played by the Mitf protein in nerve repair processes in mice. This revelation holds significant promise for the development of novel therapies aimed at improving nerve repair functions, potentially benefiting the millions of individuals afflicted by this debilitating condition.

Peripheral neuropathy, a condition characterized by nerve damage outside the central nervous system (brain and spinal cord), affects more than 3 million people annually in the United States. It can result from a variety of factors, including diabetes, injuries, genetic disorders, and infections, causing pain and sensory loss. The Salk Institute researchers have achieved a significant breakthrough by identifying the Mitf protein as a key player in the repair of damaged nerves within the peripheral nervous system.

This noteworthy discovery, recently published in the journal Cell Reports, opens the door to innovative treatments aimed at enhancing the repair process and effectively addressing peripheral neuropathy.

Senior author Professor Samuel Pfaff explains their research objectives: “We sought to understand the mechanisms governing the response to damage in peripheral nerves under various conditions, such as acute trauma, genetic disorders, or degenerative diseases. Our findings reveal that Schwann cells, specialized cells in nerves responsible for safeguarding and supporting neuronal axons, enter a repair state due to a pathway mediated by the Mitf protein.”

Understanding the Peripheral Nervous System

The peripheral nervous system encompasses all the nerves branching out from the brain and spinal cord, facilitating sensation throughout our bodies. While it comprises various cell types, Pfaff and his team focus on comprehending neurons, responsible for transmitting information throughout the nervous system, and Schwann cells, which play a crucial role in protecting healthy neurons and repairing damaged ones.

Remarkably, the peripheral nervous system possesses the ability to repair damage, in contrast to the central nervous system, which lacks this capability. However, the mechanisms orchestrating this remarkable feat have remained poorly understood until now.

Exploring how Schwann cells differentiate to initiate repairs in cases of peripheral nerve damage, the researchers examined mouse models of Charcot Marie Tooth disease (CMT), a hereditary neuropathy.

Lydia Daboussi, the first author of the study, reflects on their initial expectations: “At the outset of this project, I assumed that in cases of genetic nerve degeneration disorders, cells would inevitably perish, and recovery would be impossible. However, our findings demonstrate that Mitf activates gene programs that facilitate the repair of some damage occurring in chronic disease scenarios. When these programs are switched off, disease symptoms worsen.”

The Potential of Schwann Cell Repair Programs

In mice afflicted by CMT, the researchers observed high levels of Mitf in the nuclei of Schwann cells responsible for completing repairs. This is where genetic instructions for Schwann cell identity and repair procedures are stored. Their investigation revealed that Mitf initially resides in the cytoplasm of Schwann cells but relocates to the nucleus in response to neuronal damage, where it guides the Schwann cell in executing repairs.

To confirm the crucial role of Mitf in generating repair Schwann cells, the researchers conducted experiments where Mitf was completely removed. The results showed that, in both trauma and CMT cases, nerve repair was halted in the absence of Mitf, underscoring the indispensable nature of Mitf in peripheral nerve repair and regeneration.

Daboussi draws an analogy, likening Mitf to a fire extinguisher: ever-present within Schwann cells, unnoticed until damage occurs. When damage does take place, Mitf promptly activates the cell’s repair functions.

Pfaff expresses his surprise at the finding that Mitf orchestrates repairs even in the context of a chronic disease like CMT. He envisions the potential of harnessing Schwann cell repair programs for treating chronic diseases, speculating that targeted therapeutics could stimulate more Schwann cells to repair peripheral nerve damage, ensuring the completion of repairs, even in chronic cases. Additionally, with a deeper understanding of repair mechanisms, there is the possibility of initiating repairs in the brain stem and spinal cord.

Looking ahead, the researchers plan to focus on diabetic neuropathy, the most prevalent form of peripheral neuropathy, and explore therapeutic strategies that bolster the repair pathway, generating Schwann cells programmed to repair damage, regardless of its origin—whether trauma, genetics, or gradual development over time.

Reference: “Mitf is a Schwann cell sensor of axonal integrity that drives nerve repair” by Lydia Daboussi, Giancarlo Costaguta, Miriam Gullo, Nicole Jasinski, Veronica Pessino, Brendan O’Leary, Karen Lettieri, Shawn Driscoll and Samuel L. Pfaff, 28 October 2023, Cell Reports.
DOI: 10.1016/j.celrep.2023.113282

Other authors contributing to the research include Giancarlo Costaguta, Miriam Gullo, Nicole Jasinski, Veronica Pessino, Brendan O’Leary, Karen Lettieri, and Shawn Driscoll, all from the Salk Institute.

The study received support from various sources, including the Sol Goldman Charitable Trust, Howard Hughes Medical Institute, National Institutes of Health, George E. Hewitt Fellowship, Salk Women & Science Fellowship, and Jonas Salk Fellowship.

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More about Peripheral Neuropathy Treatment

• Salk Institute
• Cell Reports Journal
• Peripheral Neuropathy Overview
• Charcot Marie Tooth Disease
• National Institutes of Health
• Howard Hughes Medical Institute
• Sol Goldman Charitable Trust