Unraveling teh Mysteries of Aging adn Protein Dysregulation
Proteins are the workhorses of our cells,meticulously carrying out essential tasks. But when these vital molecules misfold, mutate, become inactive, or overactive, they can contribute to a range of disorders, including devastating neurodegenerative diseases. Deciphering the intricate relationship between aging and protein dysfunction is crucial for developing strategies to slow, or even reverse, these debilitating conditions.
Enter proteomics, the comprehensive study of proteins – their structures, modifications, functions, and abundance. This field has witnessed remarkable advancements, fueled by the growth of powerful mass spectrometry techniques that allow scientists to identify and analyze proteins at an unprecedented molecular level.
Dr. Uma Kanta Aryal, a research associate professor at Purdue University, is at the forefront of this cutting-edge research. His work focuses on identifying and analyzing changes in protein phosphorylation patterns, particularly the phosphosites that play a meaningful role in Parkinson’s and Alzheimer’s diseases. A recent study by Aryal and his team, published in the prestigious journal Molecular & Cellular Proteomics, sheds new light on the complex interplay between aging and protein dysfunction in the brain.
aryal’s interest with proteomics began in the early 2000s during his Ph.D. studies in Japan, where he utilized proteomic techniques to investigate enzymes from a unique white-rot fungus capable of breaking down persistent aromatic compounds. His passion for proteomics continued through his post-doctoral research and ultimately led him to establish his own proteomics program at Purdue in 2019, focusing on the intricate connection between senescence, aging, and neurodegenerative diseases. “There is a lot of interest in neurodegenerative diseases, and there is a lot I can contribute to that area,” explained Aryal.
Cells possess intricate mechanisms to activate and deactivate proteins, ensuring smooth cellular processes and preventing malfunctions. Post-translational modifications, or PTMs, are critical players in this delicate regulatory system, often overlooked despite their crucial role. Phosphorylation, a common PTM, is frequently implicated in diseases. Protein hyperphosphorylation, a state of excessive phosphorylation, can lead to aberrantly active proteins in various conditions. A prime example is tau,a protein that forms neurofibrillary tangles,contributing to neuronal loss in both Alzheimer’s and Parkinson’s diseases.
Aryal’s latest study delved into the proteomes of young, middle-aged, and old mice using a refined multi-enzyme digestion approach followed by analysis through liquid chromatography–tandem mass spectrometry (LC-MS/MS). This powerful method breaks down proteins into smaller peptide fragments, allowing researchers to uncover hidden alterations – the very PTMs that offer crucial insights into cellular function. By meticulously examining these fragments, Aryal could pinpoint the subtle changes, gaining a deeper understanding of protein behavior.
“There is a precise reason for each residue being modified,” Aryal emphasized. “That’s where I got excited – it’s not only the identification of those markers but characterizing them. Are they phosphorylated? If they are phosphorylated, where are they phosphorylated and what are the dynamics? How does this phosphorylation communicate with other PTMs?”
Aryal’s findings revealed an increase in the abundance and activity of several kinases – enzymes responsible for phosphorylating proteins – alongside changes in phosphorylation levels in proteins associated with neurodegeneration, including tau, Nefh, and Dpysl2, in older mice.
“At one of these sites, the phosphorylation level goes up, while at the other the phosphorylation goes down in old mice,” Aryal revealed, highlighting the intricate balance within the cell.
This dynamic suggests that tau plays a more complex role in neurodegeneration than initially understood. While some phosphorylation events may promote disease progression, others appear to counteract it. This ongoing internal struggle within the cell underscores the vastness of what we still need to uncover about tau and its role in these debilitating conditions.
Aging, undeniably linked to an increased risk of neurodegenerative diseases, holds the key to understanding the molecular mechanisms driving these conditions. Insights gleaned from proteomics research like Aryal’s pave the way for developing innovative therapies to combat these devastating diseases. Aryal’s future research will delve into the changes in lipid profiles within the aging mouse brain and utilize genetically altered mice with Alzheimer’s or Parkinson’s in future proteomic studies to gain even deeper insights into the disease states.
What are some potential therapeutic targets that could be identified through proteomic analysis of proteins involved in age-related cognitive decline and neurodegeneration?
Archyde News interview: Unraveling the Mysteries of Aging and Protein Dysregulation with Dr. Uma Kanta Aryal
Archyde: Today, we have the pleasure of speaking with Dr. Uma Kanta Aryal, a Research Associate professor at Purdue University, who is at the forefront of proteomics research, particularly focusing on protein phosphorylation patterns in neurodegenerative diseases. Welcome,Dr. Aryal!
Dr. Uma Kanta Aryal (UKA): Thank you, I’m delighted to be here.
Archyde: Let’s dive right in. Proteins are the workhorses of our cells, but when they misfold, mutate, or malfunction, they can contribute to devastating conditions like Parkinson’s and Alzheimer’s. Can you tell us about the role of proteomics in understanding this protein dysfunction?
UKA: Absolutely. Proteomics is the comprehensive study of proteins – their structures, modifications, functions, and abundance. With the advancements in mass spectrometry techniques, we can now identify and analyze proteins at an unprecedented molecular level. This allows us to understand not just the presence of proteins, but also their post-translational modifications like phosphorylation, which plays a crucial role in protein function and dysfunction.
Archyde: Your recent study in Molecular & cellular Proteomics sheds light on the complex interplay between aging and protein dysfunction in the brain. What were your key findings?
UKA: In our study, we focused on protein phosphorylation patterns in the brain as a function of age. We identified hundreds of phosphosites that show age-dependent changes. Some of these changes are Predicted to have a meaningful role in Parkinson’s and Alzheimer’s diseases. We believe that these changes in phosphorylation patterns may contribute to age-related cognitive decline and neurodegeneration.
Archyde: That’s fascinating. How do these findings help in developing strategies to slow or reverse these conditions?
UKA: Understanding the molecular changes that occur with aging is a crucial first step.By identifying these phosphorylation changes, we can start to understand how they contribute to the onset and progression of neurodegenerative diseases. This could lead to the progress of targeted therapies to prevent or slow down these changes.As a notable example, we could possibly target the kinases or phosphatases involved in these phosphorylation events.
Archyde: Your interest in proteomics began during your Ph.D. studies in Japan.How has your journey evolved as then?
UKA: Indeed, my passion for proteomics began in the early 2000s when I was studying enzymes from a unique white-rot fungus. As then, my journey has been a continuous exploration of the proteome. After my Ph.D., I moved to the United states for my post-doctoral research, where I began to focus more on neurodegenerative diseases.In 2019, I established my own proteomics program at Purdue, focusing on the intricate connection between senescence, aging, and neurodegenerative diseases.
Archyde: what excites you most about the future of proteomics in aging research?
UKA: I’m most excited about the potential for proteomics to help us understand the aging process at a molecular level. With the advancements in technology, we can now perform deep, large-scale proteomic analyses. I believe that these studies will not only help us identify novel biomarkers for aging and age-related diseases but also provide us with novel therapeutic targets.
Archyde: Dr. Aryal, thank you for sharing your insights with us today. We look forward to hearing more about your ongoing and future work.
UKA: Thank you! It’s been a pleasure.
