Beyond the Paper: A Conversation with Dr. Youngdoo Kim

Interviewed by Dr. Paige N. McKeon, May 30, 2025

The build-up of phosphorylated, misfolded α-synuclein contributes to Parkinson’s disease, but what is the role of this protein in disease etiology and pathogenesis? To explore this question, Youngdoo Kim and colleagues, from Huda Zoghbi’s lab at Baylor College of Medicine, created two mouse lines mimicking phosphorylation of α-synuclein at two sites linked to Parkinson’s disease. The authors discovered that mutations at phosphorylation sites Y39 or S129 may play a role in initial phases of disease etiology, but these sites alone do not account for Parkinson’s-like etiology and pathogenesis. Moving forward, Kim looks forward to expanding the applications of these mouse lines.

“It felt like a bit of a gamble, and I didn’t know if anyone else was racing to make similar models. However, we continued to refine our approach and eventually identified the right targets.”

Dr. Youngdoo Kim

Can you tell us about your research journey?

I started my first lab experience as an undergraduate part-time lab technician. My job was making food vials and bottles for fruit flies (Drosophila) and keeping Drosophila lines stocked. Little insects share a similar genome with humans and replicating neurodegenerative disease phenotypes in fruit flies was a major pull for me into this field. My experience in this lab generating a Drosophila model of neurodegenerative disease (Ataxin2-polyQ) taught me a lot about Drosophila genetics.

Following this experience, I felt moved to learn more about generating mouse models, which are also important for studying neurodegenerative diseases. This led to me developing more complex models during my PhD at Seoul National University. I contributed to the creation of the caspase-cleaved tau transgenic mouse line (TauC3), which is a valuable tool for studying tau aggregation mechanisms. For my part, this enhanced my abilities in mouse model generation and characterization—skills directly applicable to my current research focus.

After completing my degrees in South Korea, I was eager to experience different research cultures and decided to pursue postdoctoral training in the United States. My experiences at the University of Washington and Baylor College of Medicine have exposed me to researchers from around the world and provided invaluable opportunities to work alongside excellent principal investigators, graduate students, and fellow postdoctoral researchers. The collaborative environment with fellow postdoctoral researchers has been particularly meaningful, as we share challenges, leverage each other's expertise, and maintain work-life balance together.

My current postdoctoral training in the Zoghbi laboratory has further refined my expertise in generating precise genetic modifications in mice. We have developed multiple α-synuclein mutant knock-in models with Parkinson’s disease-relevance (G51D, Y39E and S129D knock-in mice). The comprehensive characterization of these models—from behavioral assessments to biochemical analyses of protein modifications and aggregation—showcases my multidisciplinary approach to neurodegenerative disease research.

What interests you about this area of research?

I have always been drawn to the fundamental questions in neurodegeneration: where do these diseases start, and how do they progress? It fascinates me to study how disease-associated proteins begin to aggregate, how these aggregates spread from one brain region to another, and how that spread leads to the symptoms we see. Understanding these processes is incredibly interesting and important to me, and I certainly plan to stay in this field.

My goal is to become a principal investigator and continue meeting the needs of the research community. I want to develop new animal models that fill gaps in our knowledge, screen potential therapeutic candidates, and validate the most promising ideas in vivo. I remain excited about contributing to breakthroughs in understanding and treating neurodegenerative diseases.

What was it like developing the transgenic mouse lines for this paper?

I am driven by the idea of creating animal models that fill key gaps in our understanding, and the emergence of CRISPR-Cas9 technology has opened doors to many new possibilities for creating knock-in mouse models in neurodegenerative disease research. Interestingly, at the time we began, no one had created a knock-in mouse with certain mutations in α-synuclein, even though models for other proteins (like amyloid-beta precursor protein for Alzheimer’s and Leucine-rich repeat kinase 2 for Parkinson’s) were being developed. We decided to take a chance and pursue it.

In our study, we focused on generating knock-in mice with phospho-mimetic mutations in the α-synuclein gene (specifically the Y39E and S129D mutations). Using CRISPR-Cas9, we designed specific changes in the endogenous mouse α-synuclein gene. In the end, these new knock-in models allowed us to make novel observations. For example, new Y39E and S129D lines gave us clues about how phosphorylation might affect α-synuclein localization in neurons.

The process had its challenges. Early on, I generated knock-in mice for other mutations (A30P and E46K) that, unfortunately, did not show any obvious disease phenotype. That was frustrating and made me worry if our efforts were in vain. It felt like a bit of a gamble, and I didn’t know if anyone else was racing to make similar models. However, we continued to refine our approach and eventually identified the right targets. When we finally confirmed that the new Y39E and S129D knock-in mice were successfully created, I felt an immense sense of relief and pride. It was incredibly rewarding to know that these models will contribute something new to the field.

What do you see as the major implication of your work?

The major implication of our work is that we have created the first mouse lines expressing phospho-mimetic forms of α-synuclein at the endogenous locus. This provides a new and more physiologically relevant way to study α-synuclein phosphorylation in vivo. Previous studies of phosphorylated α-synuclein mostly used overexpression systems, which do not reflect the normal levels of the protein in cells. With our knock-in models, we found that the phospho-mimetic mutations cause α-synuclein to become more cytosolic and less membrane-bound in neurons. This finding contributes to an ongoing debate in the field about how phosphorylation affects α-synuclein’s localization and function.

In short, our work offers new insights into how α-synuclein behaves in living brains. By suggesting that phosphorylated α-synuclein may be preferentially cytosolic, we provide a basis for further investigation of its role in disease. These models will be valuable tools for the Parkinson’s disease research community, enabling more accurate studies of α-synuclein phosphorylation and its effects on neuron biology and pathology.

How was your experience with the eNeuro review process?

My experience with eNeuro was largely positive. It felt similar to other journals in that we went through two rounds of reviews. In the first round, one reviewer asked for a large number of additional experiments—experiments that could have taken another year to complete. Fortunately, the editor at eNeuro helped us find a good balance so we could explain our work clearly without needing to do every single suggested experiment. What impressed me was the speed of publication after acceptance. Once our manuscript was accepted, it was published within a week! That was extremely fast compared to most journals I’ve seen, and it was a very pleasant surprise.

Are there future directions for this project that we should all stay tuned for?

Building on our diverse knock-in mouse models, we aim to expand the scientific applications of these tools. Currently, we're testing several compounds in the field to evaluate whether our models can serve as effective platforms for drug validation. Additionally, we're investigating the effects of other Parkinson's disease risk factor genes by creating crosses between our mouse lines and other genetically modified strains. These efforts will help establish our models as valuable resources for the broader research community.

Read the full article:

Alpha-Synuclein Phosphomimetic Y39E and S129D Knock-In Mice Show Cytosolic Alpha-Synuclein Localization without Developing Neurodegeneration or Motor Deficits
YoungDoo Kim, Bhupesh Vaidya, Joseph McInnes, and Huda Y. Zoghbi