Understanding IMPDH2 Aggregates and Their Role in Neurodegeneration

Hiab working in a lab.



Assistant Professor of Pathology and Laboratory Medicine

Project Summary

This summer, I worked on my research project in the Aquizu lab at the Children’s Hospital of Philadelphia. This project is focused on understanding the genetic origins of Pontocerebellar Hypoplasia Type 9 (PCH-9). Patients with PCH-9 display neurodevelopmental deficits as well as neurodegeneration. Mutations in Adenosine Monophosphate Deaminase 2 (AMPD2) gene which regulates the conversion of adenosine monophosphate (AMP) to inosine monophosphate (IMP) during nucleotide metabolism pathway is important for proper brain development. The mutations in AMPD2 gene alters the levels of Inosine Monophosphate Dehydrogenase 2 (IMPDH2) and induces its polymerization into micron-length aggregates with rod and ring structures. The goal of this project is to investigate how IMPDH2 aggregates resulted in changes to the brain structure, survival, and weight loss in the PCH-9 mice models. For this, we have generated mice that carry a non-polymerizing for of IMPDH2 generated by the substitution of the tyrosine in position 12 to an alanine (IMPDH2-Y12A). This project was focused on the characterization of the IMPDH2-Y12A mutated mice and the AMPD2 mutated mice in order to uncover the role of IMPDH2 rod and ring aggregates in neurodegeneration.

Through this experience, I was able to learn more experimental protocols as well as interact more with the mice models. Many of the experiments that were completed involved the quantification of various proteins which required me to learn not only the experimental methodology but also, learning how to organize and quantify the data collected. In addition, because I was using a mice model I learned how to interact with the mice through learning how to breed, sacrifice, weigh, and collect samples from mice. While I worked on my project, I also read papers on different experimental protocols, and presented in lab meetings which helped me gain more knowledge on my research project.

My research experience has proved invaluable experience not only because of the hands-on bench work and animal handling techniques I learned but, also the opportunity to engage with lab members at different stages of their career paths. 

My research project has been very fulfilling because of my passion and desire to work on understanding and treating neurodegenerative disorders. It has been great to observe and learn how scientific concepts and experiments that I once learned in my classes were being applied in the lab setting. The work in the lab is crucial because many of the children with this disorder pass away at young ages and through understanding the molecular mechanism of neuro-degeneration in this disease model, it is possible to understand other neuro-degenerative diseases. Through this project, I am inspired to continue my career goal to become a physician researcher and study the brain.