Dr. Springer's Translational Cell Biology of Parkinson's Disease Lab has studied a series of missense mutations in PINK1 and PRKN (Parkin) that enable researchers to understand the molecular mechanisms of the pathway and its individual sequential steps, and to determine the pathogenicity of variants of unknown significance. The research team uses computational structural modeling to understand the specific molecular effects of genetic variants in PINK1 and Parkin and validate the findings in cell-based and biochemical assays. The team studies fibroblasts and directly converted (transdifferentiated) neuron cells under endogenous conditions.
Dr. Springer's team has discovered that certain heterozygous mutations can present risk factors for late-onset Parkinson's disease, further highlighting the importance of the pathway. This approach is also being used for a structure- and function-function based drug design and high-throughput screening of small molecules.
- Caulfield TR, Fiesel FC, Moussaud-Lamodière EL, Dourado DF, Flores SC, Springer W. Phosphorylation by PINK1 releases the UBL domain and initializes the conformational opening of the E3 ubiquitin ligase Parkin. PLOS Computational Biology. 2014;10:e1003935.
- Caulfield TR, Fiesel FC, Springer W. Activation of the E3 ubiquitin ligase Parkin. Biochemical Society Transactions. 2015;43:269.
- Siuda J, Jasinska-Myga B, Boczarska-Jedynak M, Opala G, Fiesel FC, Moussaud-Lamodière EL, Scarffe LA, Dawson VL, Ross OA, Springer W, Dawson TM, Wszolek ZK. Early-onset Parkinson's disease due to PINK1 p.Q456X mutation — Clinical and functional study. Parkinsonism and Related Disorders. 2014;20:1274.
- Fiesel FC, Caulfield TR, Moussaud-Lamodière EL, Ogaki K, Dourado DF, Flores SC, Ross OA, Springer W. Structural and functional impact of Parkinson disease-associated mutations in the E3 ubiquitin ligase Parkin. Human Mutation. 2015;36:774.
- Ando M, Fiesel FC, Hudec R, Caulfield TR, Ogaki K, Górka-Skoczylas P, Koziorowski D, Friedman A, Chen L, Dawson VL, Dawson TM, Bu G, Ross OA, Wszolek ZK, Springer W. The PINK1 p.I368N mutation affects protein stability and ubiquitin kinase activity. Molecular Neurodegeneration. 2017;12:32.
- Puschmann A, Fiesel FC, Caulfield TR, Hudec R, Ando M, Truban D, Hou X, Ogaki K, Heckman MG, James ED, Swanberg M, Jimenez-Ferrer I, Hansson O, Opala G, Siuda J, Boczarska-Jedynak M, Friedman A, Koziorowski D, Aasly JO, Lynch T, Mellick GD, Mohan M, Silburn PA, Sanotsky Y, Vilariño-Güell C, Farrer MJ, Chen L, Dawson VL, Dawson TM, Wszolek ZK, Ross OA, Springer W. Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism. Brain. 2017;140:98.