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Proteins, the versatile workhorses of life, serve myriad functions crucial to the sustenance of organisms. However, when proteins misfold, they not only fail in their tasks but also pose a threat by accumulating and disrupting cellular processes. These misfolded proteins are implicated in various degenerative diseases, including Alzheimer’s, Parkinson’s, and retinitis pigmentosa, for which effective treatments remain elusive.
In a groundbreaking study conducted at UC Santa Barbara, researchers have unveiled a novel connection between a specific ion transport protein and the cellular machinery responsible for disposing of misfolded proteins. The findings, published in Developmental Cell, pinpoint a promising target for combating these debilitating conditions.
Lead author Denise Montell, Duggan Professor and Distinguished Professor in the Department of Molecular, Cellular, and Developmental Biology at UC Santa Barbara, expressed optimism about the study’s implications: “By delving into basic cell biology using fruit fly ovaries as a model system, we unexpectedly uncovered a potential avenue for preventing neurodegeneration, with significant implications for the treatment of certain human diseases.”
For over three decades, Montell’s laboratory has focused on investigating cell movement in fruit fly ovaries, providing valuable insights into fundamental cellular behaviors underlying processes such as embryonic development, wound healing, and tumor metastasis.
Central to the study is the gene ZIP7, which encodes a protein responsible for transporting zinc ions within cells. ZIP7’s role is pivotal, as zinc ions play essential roles in protein structure and function across various organisms. Remarkably, ZIP7’s conservation across evolutionary time underscores its fundamental significance in cellular processes.
The study elucidates ZIP7’s involvement in mitigating endoplasmic reticulum (ER) stress induced by misfolded proteins. When cells experience ER stress, their mobility is impaired, exacerbating the cellular dysfunction associated with degenerative diseases. However, overexpression of ZIP7 effectively alleviated ER stress and restored cellular mobility, offering a potential therapeutic strategy.
Further investigations revealed that ZIP7 facilitates the removal of ubiquitin tags from misfolded proteins, thereby enabling their degradation by proteasomes, the cellular “garbage disposals.” Crucially, the study identified zinc as a critical factor in this process, highlighting ZIP7’s role in supplying zinc to an enzyme called Rpn11, which is essential for ubiquitin removal.
The implications of these findings extend beyond fruit fly ovaries, as evidenced by experiments demonstrating ZIP7’s potential to prevent retinal degeneration and blindness in fruit flies with mutations associated with retinitis pigmentosa. Collaborative efforts with Professor Dennis Clegg aim to validate these findings in human retinal organoids, offering hope for the development of effective treatments.
Montell emphasized the transformative potential of this discovery: “This research exemplifies the power of curiosity-driven inquiry, where scientific exploration aimed at understanding fundamental biological processes can unexpectedly lead to groundbreaking therapeutic interventions, possibly offering cures for multiple diseases.”
The study underscores the invaluable contributions of basic research in uncovering novel pathways for combating degenerative diseases, offering renewed hope for patients and researchers alike.
Source:
University of California – Santa Barbara
