Proteins play a vital role in life, serving as the essential components for building, signaling, processing, transporting, and catalyzing various functions within organisms. The structure of a protein is crucial to its function, and when proteins are misshapen, they are unable to perform their duties and can even disrupt the normal functions of cells. This leads to a range of degenerative diseases, such as Alzheimer’s, Parkinson’s, and retinitis pigmentosa, for which there are currently no cures.Proteins are vital for carrying out functions in the body, but when they are misfolded they can cause a build-up of toxins and lead to degenerative diseases such as Alzheimer’s and Parkinson’s. A study from UC Santa Barbara has found a link between a specific ion transport protein and the cell’s ability to dispose of misfolded proteins. This could potentially lead to new treatments for currently incurable diseases like retinitis pigmentosa. The findings were published in the journal D.New research published in Developmental Cell has discovered a potential target for treating debilitating conditions such as neurodegeneration. The study, conducted on fruit fly ovaries, found a way to prevent neurodegeneration and believes it could have applications in treating human diseases. Denise Montell, the senior author and Duggan Professor in the Department of Molecular, Cellular, and Developmental Biology, stated that her lab has been studying cell movement in fruit fly ovaries for 35 years, and believes it provides a great model for understanding cell mobility.The research has shown that this particular gene, ZIP7, plays a crucial role in various cellular processes such as embryonic development, wound healing, and tumor metastasis. This makes understanding its behavior a top priority for scientists. The focus of the study is on the ZIP7 gene, which produces a protein of the same name. Previous research by Montell’s team had identified a mutation in this gene that affected cell mobility, which caught their interest. The ZIP7 protein is responsible for transporting zinc ions within a cell. These ions are rare in the cytoplasm but are abundant in proteins, where they play a role in the structure and function.catalyzing chemical reactions. According to Montell, ZIP7 is present in plants, yeast, flies, and humans, indicating its fundamental importance over a long period of time.
ZIP7 serves as the sole zinc transporter in the endoplasmic reticulum, a cellular structure responsible for producing proteins intended for the cell’s outer membrane or for secretion. This is where approximately one-third of our proteins are synthesized.
In this study, ZIP7 is the main focus, while the theme revolves around misfolded proteins and their disposal. The function of proteins is dependent on their structure.It is not sufficient to just have the correct ingredients, a protein also needs to fold in the right way in order to function properly. When proteins misfold, it can lead to various diseases and disorders.
Even in a healthy cell, proteins can sometimes misfold. Thankfully, cells have a system in place to address this issue. If the misfolding is minor, the cell can attempt to refold the protein. Otherwise, it will label the misfolded molecule with a small protein called ubiquitin and remove it from the endoplasmic reticulum (ER) for recycling.
Within the cytoplasm, there are proteasomes, which act as the “garbage disposals” of the cell. They essentially break down the misfolded proteins.he protein is broken down into small fragments that can be recycled,” Montell explained. “However, if the cell’s waste disposal system is overwhelmed, such as by an excessive amount of potato peels, it can lead to ER stress.” This stress prompts a reaction that slows down protein production and increases the number of proteasomes to clear the waste buildup. If these measures are unsuccessful, the cell will undergo programmed death.
Additionally, Xiaoran Guo, a co-lead author and former Ph.D. student of Montell, observed that the lack of ZIP7 led to ER stress in the fruit fly’s ovary. She then conducted research to determine the effects of this stress.The reason for the loss of cell mobility was due to ER stress induced by a misfolded protein. When a different misfolded protein was used to induce ER stress, it also resulted in impaired cell migration.
Guo found that when ZIP7 was over-expressed in these cells, the backlog of misfolded proteins disappeared, ER stress was resolved, and the cells regained their mobility. Guo was surprised by the results and questioned if everything was done correctly. She also noted that ZIP7 alone seemed to be highly effective in resolving ER stress.
Additionally, the misfolded protein used, rhodopsin, did not contain zinc in its structure. This led Guo to suspect that ZIP7 played a role in resolving ER stress.It is evident that ZIP7 plays a role in the degradation process. Morgan Mutch, a co-lead author and doctoral student, conducted an experiment using a drug to inhibit the proteasome from breaking down misfolded rhodopsin. The results showed that this action counteracted the positive effects of ZIP7, leading to the conclusion that ZIP7 acts before the proteasome degradation of the misfolded protein.
The authors conducted experiments with four modified ZIP7 genes, two of which disrupted the protein’s zinc-carrying ability, while the other two did not. They found that zinc transport was crucial in reducing ER stress.
In the midst of this discovery, a new player comes into play.The article discusses the role of the enzyme Rpn11 in the proteasome and its relationship with misfolded proteins. It explains how Rpn11 is responsible for removing ubiquitin tags from misfolded proteins, allowing them to enter the proteasome for breakdown. The article also mentions the importance of zinc for Rpn11 to perform its function.
The researcher, Mutch, expresses surprise and excitement at the discovery that increasing ZIP7 expression can prevent the accumulation of ubiquitin-tagged proteins. This finding was unexpected and highlights the critical role of ZIP7 in the process.Using zinc to activate Rpn11 allows it to remove the labels from faulty proteins, helping them to fit into the structure that breaks them down. Inhibiting the Rpn11 enzyme supported this idea.
“The feeling of discovering something new, something that no one has discovered before, is the best feeling for a scientist,” Mutch remarked.
A possible treatment
The findings indicate that increasing the expression of ZIP7 could serve as a potential treatment for various diseases. For example, misfolded rhodopsin leads to retinitis pigmentosa, a hereditary vision loss condition that currently has no cure. The researchers have created a strain of fruit flies carrying a mutation that causes a disease similar to retinitis pigmentosa. They then increased the expression of the ZIP7 gene in these flies to study its effects. According to Montell, the results showed that overexpression of ZIP7 prevented retinal degeneration and blindness in these flies. Typically, all the flies with the mutant rhodopsin gene develop retinitis pigmentosa, but when overactive ZIP7 was introduced, 65% of the flies had eyes that responded normally to light. Montell’s lab is now working with Professor Dennis Clegg at UC Santa Barbara to further explore the impact of ZIP7 in human retinal organoids, which are tissue cultures with a mutation similar to the one in the fruit flies.The cause of retinitis pigmentosa is being investigated in a project that was initially funded by the National Institute for General Medical Sciences and will now receive a $900,000 grant from the Foundation Fighting Blindness for the next three years. This funding will allow researchers to test the theory that ZIP7 gene therapy can prevent blindness in patients with retinitis pigmentosa.
Additionally, the decline in proteasome capacity as we age contributes to many common signs of aging and increases the likelihood of age-related degenerative diseases. Therapies targeting ZIP7 could potentially slow the development or progression of these ailments.nts and also produced promising results in extending the lifespan of fruit flies.
“This is a prime example of research driven by curiosity,” said Montell. “You study something simply because it’s interesting, and as you follow the data, you end up discovering something you never set out to study, possibly even a cure for multiple diseases.”
