In the Jomaa Lab at UVA Health, researchers work to understand the relationship between protein aggregation and neurodegenerative diseases. Unlocking this mystery means understanding exactly how newly formed proteins reach their final destinations in the body to fulfill their designated roles. Disruptions to these processes causes protein aggregation, which in turn causes disease.
Specifically, these disruptions play a role in congenital disorders of glycosylation. This group of genetic disorders can cause physical and cognitive disabilities and life-threatening medical issues. Researchers believe a better understanding of the mutations in ER protein translocation and processing complexes that happen in these conditions will lead to better treatments.
Watch Ahmad Jomaa, PhD, talk about his research and read his answers to our questions below.
What are you working on right now?
My lab is investigating the various mechanisms of protein sorting and translocation across organelle membranes, with a specific focus on the endoplasmic reticulum and mitochondria. Proper localization of proteins to subcellular compartments is a fundamental process essential for maintaining cellular and organelle proteostasis.
Interestingly, sorting of newly made proteins begins during their synthesis on ribosomes. This sorting is guided by molecular “zip codes” embedded within the primary sequences of these proteins. My lab’s research aims to elucidate the processes that regulate the localization and targeting of these nascent proteins to their appropriate organelles. We are particularly interested in the role of chaperones in sorting newly synthesized proteins within the cytoplasm and facilitating their delivery for subsequent import.
We employ an integrative approach that combines molecular and structural biology, biochemistry, biophysics, and cell biology. We use cell-free protein synthesis and protein biochemistry techniques to isolate complexes involved in protein targeting and translocation. We then use high-resolution cryo-electron microscopy to determine the structures of these complexes and to elucidate the molecular interactions at atomic resolution.
Complementary functional studies, conducted both in vitro and in cells, serve to validate and enhance our structural observations. This comprehensive strategy enables us to gain a detailed understanding of the mechanisms underlying protein sorting and translocation, advancing our knowledge of cellular and organelle proteostasis.
What are the most intriguing potential clinical applications of your work?
Dysfunction in nascent protein targeting or localization can result in protein misfolding and then aggregation. If aggregation is not cleared, it can lead to disease in humans. Protein aggregation is a hallmark of neurodegeneration and is implicated in pathophysiology of neurodegenerative diseases.
Notably, mutations in ER protein translocation and processing complexes have been linked to a group of genetic disorders known as congenital disorders of glycosylation (CDG). CDG manifests as a neurodegenerative disease with early onset, characterized by brain malformations such as atrophic changes in the cerebellum and cerebrum. Neurological symptoms include psychomotor retardation, cognitive disorders, microcephaly, epileptic seizures, hypotonia, ataxia, polyneuropathy, and stroke-like events.
At the molecular level, CDG arises from disruptions in the glycosylation process of proteins in the endoplasmic reticulum (ER), affecting both organelle and cell homeostasis. Glycosylation involves the addition of sugar moieties to a wide range of ER proteins and secreted hormones. This modification is crucial for the development, growth, and functioning of our body and predominantly takes place during protein synthesis. Unfortunately, the molecular mechanism underlying this process and it's malfunctions in CDG are still not known.
On the other hand, impaired mitochondrial protein import has been associated with both Alzheimer's and Parkinson's diseases. In familial Parkinson's patients, for example, mutations in PINK1/PARKIN can limit the cell's ability to clear dysfunctional mitochondria due to impaired mitophagy. One of these causes is likely due to defects in proper import and processing of PINK1 at the mitochondrial membrane, which is key for the activation of PARKIN. This dysfunction leads to the accumulation of unfolded proteins in the mitochondrial matrix and likely contributes to the physiology of the disease.
What discovery, paper, or presentation impacted the way you think?
Doing research is always exciting and we are constantly impacted by discoveries either in our field of study or unrelated but still equally interesting fields. These discoveries are either technical advancements or major breakthroughs that answer long-standing questions in biology. I have been fortunate to experience both throughout my training and in my lab.
One significant technical advancement that had a profound influence on my career occurred nearly 10 years ago with the introduction of new hardware that revolutionized cryo-electron microscopy. This innovation transformed the field of structural biology, enabling EM scientists suddenly to move from interpreting indistinct protein blobs to visualizing molecular interactions at atomic detail. This technological leap was recognized with the 2017 Nobel Prize in Chemistry, awarded to key researchers who advanced the technology to its current state.
What made you choose UVA Health as the place to do your research?
UVA Health aligned perfectly with my research interests in understanding the process of nascent proteins sorting and translocation across organelle membranes. UVA Health boasts a renowned neuroscience research program, which provides a rich environment for collaboration and also offers opportunities to engage with cutting-edge research in neurobiology and related disciplines.
The faculty are known for their collegiality and approachability, creating a supportive atmosphere that fosters teamwork and interdisciplinary collaboration. This is crucial for advancing complex research topics like protein sorting, where insights from diverse perspectives can lead to breakthrough discoveries.
Located in central Virginia, UVA Health is in close proximity to major research hubs and academic institutions. For my group, this advantage enhances opportunities for networking, attending seminars, and collaborating with experts across various fields. The exposure to diverse research environments and perspectives enriches the research experience and opens avenues for exploring new methodologies and approaches.
Furthermore, a strong emphasis on basic science provides a solid foundation for integrating molecular biology with physiology and disease models. This integrated approach is essential for unraveling the intricate mechanisms underlying protein sorting and its implications in health and disease. By bridging these disciplines, UVA Health offers an excellent platform to translate fundamental research findings into clinical applications that can benefit patients.
