Disease Relevance of Mitophagy
The Translational Cell Biology of Parkinson's Disease Lab at Mayo Clinic has created a toolbox to monitor activation of the pathway and follow its flux through the autophagic-lysosomal system in cell lines, in neurons and in tissues. Using emerging, detailed biological knowledge, the lab develops novel biomarkers and small molecule therapeutics for diseases where mitochondrial, autophagic and lysosomal dysfunctions appear as a common theme.
Using cellular and mouse models as well as human postmortem brain samples, Dr. Springer's research team is analyzing the relevance of PINK1- and PRKN (Parkin)-directed mitophagy in stress conditions, aging and disease. The lab has recently developed novel antibodies that specifically detect phosphorylated ubiquitin, which serves as a selective, quantitative label of damaged mitochondria. Phosphorylated ubiquitin levels increase upon pathophysiologically relevant mitochondrial stress or lysosomal blockade and are elevated in brain samples from aged and diseased individuals. The research team is working to optimize biomarker assays on a Meso Scale Discovery platform to analyze biofluids of people with PD, including blood and cerebrospinal fluid.
- Watzlawik JO, Hou X, Fricova D, Ramnarine C, Barodia SK, Gendron TF, Heckman MG, DeTure M, Siuda J, Wszolek ZK, Scherzer CR, Ross OA, Bu G, Dickson DW, Goldberg MS, Fiesel FC, Springer W. Sensitive ELISA-based detection method for the mitophagy marker p-S65-Ub in human cells, autopsy brain, and blood samples. Autophagy. 2021; doi:10.1080/15548627.2020.1834712.
- Hou X, Watzlawik JO, Cook C, Liu CC, Kang SS, Lin WL, DeTure M, Heckman MG, Diehl NN, Al-Shaikh FSH, Walton RL, Ross OA, Melrose HL, Ertekin-Taner N, Bu G, Petrucelli L, Fryer JD, Murray ME, Dickson DW, Fiesel FC, Springer W. Mitophagy alterations in Alzheimer's disease are associated with granulovacuolar degeneration and early tau pathology. Alzheimer's & Dementia. 2020; doi:0.1002/alz.12198.
- Fiesel FC, Ando M, Hudec R, Hill AR, Castanedes-Casey M, Caulfield TR, Moussaud-Lamodière EL, Stankowski JN, Bauer PO, Lorenzo-Betancor O, Ferrer I, Arbelo JM, Siuda J, Chen L, Dawson VL, Dawson TM, Wszolek ZK, Ross OA, Dickson DW, Springer W. (Patho-)physiological relevance of PINK1-dependent ubiquitin phosphorylation. EMBO Reports. 2015; doi:10.15252/embr.201540514.
- Fiesel FC, Springer W. Disease relevance of phosphorylated ubiquitin (p-S65-Ub). Autophagy. 2015; doi:10.1080/15548627.2015.1091912.
- Hou X, Fiesel FC, Truban D, Castanedes Casey M, Lin WL, Soto AI, Tacik P, Rousseau LG, Diehl NN, Heckman MG, Lorenzo-Betancor O, Ferrer I, Arbelo JM, Steele JC, Farrer MJ, Cornejo-Olivas M, Torres L, Mata IF, Graff-Radford NR, Wszolek ZK, Ross OA, Murray ME, Dickson DW, Springer W. Age- and disease-dependent increase of the mitophagy marker phospho-ubiquitin in normal aging and Lewy body disease. Autophagy. 2018; doi:1080/15548627.2018.1461294.
- Fiesel FC, James ED, Hudec R, Springer W. Mitochondrial targeted HSP90 inhibitor Gamitrinib-TPP (G-TPP) induces PINK1/Parkin-dependent mitophagy. Oncotarget. 2017; doi:10.18632/oncotarget.22287.