Our understanding of cellular MAGEL2 functions in brain development and SYS pathophysiology is limited due to insufficient data on cell type-specific and development- dependent MAGEL2 expression patterns. Dr. Althammer's project will provide unprecedented information about RNA expression patterns in a time and cell type-specific manner, which will serve as a valuable resource for the SYS community. Analysis of gene and protein expression during different times a day will help us to understand how MAGEL2 and other proteins are dependent on the circadian rhythm. Overall, these data will be important for our better understanding of the onset and pathophysiology of SYS and provide critical insights into impaired genes and proteins, which could be translated into clinical approaches.
Lay Abstract
Truncating mutations of the MAGEL2 protein cause Schaaf-Yang syndrome. However, we currently lack critical information about the exact cell types that express MAGEL2 and about its role during brain development. Thus, our understanding of cellular MAGEL2 functions in brain development and SYS pathophysiology is limited due to insufficient data on cell type-specific and development-dependent MAGEL2 expression patterns. To address this gap in our knowledge, our proposal aims to answer four pivotal points through single cell and bulk RNA sequencing, as well as protein analysis at different developmental stages and times of the day:
1. Identify Magel2-expressing cell types in developing and adult hypothalamus.
2. Investigate transient Magel2 expression during brain development.
3. Determine if Magel2/Magel2 expression is regulated by circadian rhythm and its consistency throughout life.
4. Examine intracellular consequences of truncated Magel2 protein.
Our project will provide unprecedented information about RNA expression patterns in a time and cell type-specific manner, which will serve as a valuable resource for the SYS community. The analysis of gene and protein expression during different times a day will help us to understand how MAGEL2 and other proteins are dependent on the circadian rhythm. Overall, these data will be important for our better understanding of the onset and pathophysiology of SYS and provide critical insights into impaired genes and proteins, which could be translated into clinical approaches. While this project does not directly relate to a clinical study, very limited information about gene or protein expression levels in SYS is currently available, highlighting the need for unbiased transcriptomic and proteomic data. Follow-up experiments could include a more detailed analysis of dysregulated proteins and behavioral (and molecular) rescue experiments in the novel SYS rat model, which would be based on our findings.