Faculty Profile

Dr. Frank F. Soldner, M.D.

Frank F. Soldner, M.D.

Assistant Professor, Dominick P. Purpura Department of Neuroscience

Assistant Professor, Department of Genetics

Professional Interests

A significant challenge of studying complex human diseases is the lack of relevant model systems that combine know genetic elements with disease-associated phenotypic readouts. This is particularly problematic for sporadic neurodegenerative diseases that have no well-defined genetic etiology and do not follow Mendelian inheritance patterns. Epidemiology and population genetics suggest that such diseases result from a complex interaction between multiple risk factors, both genetic and non-genetic (lifestyle and environmental). Although genome wide association studies (GWAS) have identified genomic variations, such as single nucleotide polymorphisms (SNPs), deletions, and insertions associated with a higher risk to develop specific neurological disorders, the vast majority of such sequence variants have no established biological relevance to disease or clinical utility to prognosis or treatment.

Three major recent innovations have fundamentally changed our ability to study human neurological disorders in a cell culture dish: (i) Reprogramming of somatic cells into human induced pluripotent stem cells (hiPSCs) to generate patient-derived disease-relevant neuronal cells, (ii) the development of genome engineering technologies such as the CRISPR/Cas9 system to modify the genome in human cells, and (iii) the availability of tissue-type and disease-specific genome-scale genetic and epigenetic information. Our previous work demonstrated that an interdisciplinary approach, integrating these technologies, enables us to study neurological disorders in a genetically controlled and systematic manner in human neuronal cells. Using these previously unavailable molecular and cellular tools, we were able to dissect the functional role of diseases-associated sequence variations in non-coding regulatory elements such as distal enhancer sequences in the pathogenesis of Parkinson’s disease. My lab is extending this novel experimental framework in human pluripotent stem cell (hPSC)-derived two-dimensional (2D) monolayer and three-dimensional (3D) organoid neuronal culture systems to systematically investigate the genetic, cellular, and molecular basis of neurodegenerative disorders. We are establishing robust disease-relevant phenotypic readouts to perform unbiased compound and CRISPR/Cas9-based genome-scale genetic screens and will exploit these approaches to understand how genetic, epigenetic, and environmental factors contribute to the development and progression of neurological diseases.

Selected Publications

Most relevant publications:

Soldner, F. & Jaenisch, R. Stem Cells, Genome Editing, and the Path to Translational Medicine. Cell, 175, 615-632 (2018)

Soldner, F., Stelzer, Y., Shivalila, C. S., Abraham, B. J., Latourelle, J. C., Barrasa, M. I., Goldmann, J., Myers, R. H., Young, R. A. & Jaenisch, R. Parkinson-associated risk variant in distal enhancer of α-synuclein modulates target gene expression. Nature 533, 95–99 (2016).

Soldner, F., Laganière, J., Cheng, A. W., Hockemeyer, D., Gao, Q., Alagappan, R., Khurana, V., Golbe, L. I., Myers, R. H., Lindquist, S., Zhang, L., Guschin, D., Fong, L. K., Vu, B. J., Meng, X., Urnov, F. D., Rebar, E. J., Gregory, P. D., Zhang, H. S. & Jaenisch, R. Generation of Isogenic Pluripotent Stem Cells Differing Exclusively at Two Early Onset Parkinson Point Mutations. Cell 146, 318–331 (2011).

Soldner, F.*, Hockemeyer, D.*, Beard, C., Gao, Q., Bell, G. W., Cook, E. G., Hargus, G., Blak, A., Cooper, O., Mitalipova, M., Isacson, O. & Jaenisch, R. Parkinson's disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell 136, 964–977 (2009).

Hockemeyer, D.*, Soldner, F.*, Beard, C., Gao, Q., Mitalipova, M., Dekelver, R. C., Katibah, G. E., Amora, R., Boydston, E. A., Zeitler, B., Meng, X., Miller, J. C., Zhang, L., Rebar, E. J., Gregory, P. D., Urnov, F. D. & Jaenisch, R. Efficient targeting of expressed and silent genes in human ESCs and iPSCs using zinc-finger nucleases. Nat Biotechnol 27, 851–857 (2009).

Hockemeyer, D.*, Soldner, F.*, Cook, E. G., Gao, Q., Mitalipova, M. & Jaenisch, R. A drug-inducible system for direct reprogramming of human somatic cells to pluripotency. Cell Stem Cell 3, 346–353 (2008).

(* Equally contributing authors)


Additional publications:

Fanning, S., Haque, A., Imberdis, T., Baru, V., Barrasa, M. I., Nuber, S., Termine, D., Ramalingam, N., Ho, G. P. H., Noble, T., Sandoe, J., Lou, Y., Landgraf, D., Freyzon, Y., Newby, G., Soldner, F., Terry-Kantor, E., Kim, T. E., Hofbauer, H. F., Becuwe, M., Jaenisch, R., Pincus, D., Clish, C. B., Walther, T. C., Farese, R. V. Jr., Srinivasan, S., Welte, M. A., Kohlwein, S. D., Dettmer, U., Lindquist, S., Selkoe, D. Lipidomic Analysis of α-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson. Mol Cell 73, 1001-1014 (2019) 

Oh, C.-K., Sultan, A., Platzer, J., Dolatabadi, N., Soldner, F., McClatchy, D. B., Diedrich J.K., Yates J.R. 3rd, Ambasudhan R., Nakamura T., Jaenisch R., Lipton S.A. S-Nitrosylation of PINK1 Attenuates PINK1/Parkin- Dependent Mitophagy in hiPSC-Based Parkinson’s Disease Models. Cell Reports 21(8), 2171–2182. (2017)

Brennand, K. J., Marchetto, M. C., Benvenisty, N., Brüstle, O., Ebert, A., Izpisúa Belmonte, J. C., Kaykas, A., Lancaster, M. A., Livesey, F. J., McConnell, M. J., McKay, R. D., Morrow, E. M., Muotri, A. R., Panchision, D. M., Rubin, L. L., Sawa, A., Soldner, F., Song, H., Studer, L., Temple, S., Vaccarino, F. M., Wu, J., Vanderhaeghen, P., Gage, F. H. & Jaenisch, R. Creating Patient-Specific Neural Cells for the In Vitro Study of Brain Disorders. Stem Cell Reports 5, 933–945 (2015).

Stelzer Y., Shivalila C.S., Soldner F., Markoulaki S. & Jaenisch R.  Tracing dynamic changes of DNA methylation at single-cell resolution. Cell 163, 218-29 (2015).

Dettmer U., Newman A.J., Soldner F., Luth E.S., Kim N.C., von Saucken V.E., Sanderson J.B., Jaenisch R., Bartels T. & Selkoe D. Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation. Nat Commun, 7314 (2015).

Soldner F. & Jaenisch R. Dissecting risk haplotypes in sporadic Alzheimer's disease. Cell Stem Cell 16, 341-2 (2015)

Flierl A., Oliveira L.M., Falomir-Lockhart L.J., Mak S.K., Hesley J., Soldner F., Arndt-Jovin D.J., Jaenisch R., Langston J.W., Jovin T.M. & Schüle B. Higher vulnerability and stress sensitivity of neuronal precursor cells carrying an alpha-synuclein gene triplication. PLoS One 9, e112413 (2014).

Ryan, S. D., Dolatabadi, N., Chan, S. F., Zhang, X., Akhtar, M. W., Parker, J., Soldner, F., Sunico, C. R., Nagar, S., Talantova, M., Lee, B., Lopez, K., Nutter, A., Shan, B., Molokanova, E., Zhang, Y., Han, X., Nakamura, T., Masliah, E., Yates, J. R., III, Nakanishi, N., Andreyev, A. Y., Okamoto, S.-I., Jaenisch, R., Ambasudhan, R. & Lipton, S. A. Isogenic Human iPSC Parkinson’s Model Shows Nitrosative Stress-InducedDysfunction in MEF2-PGC1a Transcription. Cell 155, 1351–1364 (2013).

Chung, C. Y., Khurana, V., Auluck, P. K., Tardiff, D. F., Mazzulli, J. R., Soldner, F., Baru, V., Lou, Y., Freyzon, Y., Cho, S., Mungenast, A. E., Muffat, J., Mitalipova, M., Pluth, M. D., Jui, N. T., Schüle, B., Lippard, S. J., Tsai, L.-H., Krainc, D., Buchwald, S. L., Jaenisch, R. & Lindquist, S. Identification and rescue of α-synuclein toxicity in Parkinson patient-derived neurons. Science 342, 983–987 (2013).

Torikai H., Reik A., Soldner F., Warren E.H., Yuen C., Zhou Y., Crossland D.L., Huls H., Littman N., Zhang Z., Tykodi S.S., Kebriaei P., Lee D.A., Miller J.C., Rebar E.J., Holmes M.C., Jaenisch R., Champlin R.E., Gregory P.D. & Cooper L.J. Toward eliminating HLA class I expression to generate universal cells from allogeneic donors. Blood 122, 1341-9 (2013). 

Soldner, F. & Jaenisch, R. Medicine. iPSC disease modeling. Science 338, 1155–1156 (2012).

Major, T., Menon, J., Auyeung, G., Soldner, F., Hockemeyer, D., Jaenisch, R. & Tabar, V. Transgene Excision Has No Impact on In Vivo Integration of Human iPS Derived Neural Precursors. PLoS ONE 6, e24687 (2011).

Hargus, G., Cooper, O., Deleidi, M., Levy, A., Lee, K., Marlow, E., Yow, A., Soldner, F., Hockemeyer, D., Hallett, P. J., Osborn, T., Jaenisch, R. & Isacson, O. Differentiated Parkinson patient-derived induced pluripotent stem cells grow in the adult rodent brain and reduce motor asymmetry in Parkinsonian rats. Proceedings of the National Academy of Sciences 107, 15921–15926 (2010).

Guenther, M. G., Frampton, G. M., Soldner, F., Hockemeyer, D., Mitalipova, M., Jaenisch, R. & Young, R. A. Chromatin structure and gene expression programs of human embryonic and induced pluripotent stem cells. Cell Stem Cell 7, 249–257 (2010).

Hanna, J., Cheng, A. W., Saha, K., Kim, J., Lengner, C. J., Soldner, F., Cassady, J. P., Muffat, J., Carey, B. W. & Jaenisch, R. Human embryonic stem cells with biological and epigenetic characteristics similar to those of mouse ESCs. Proceedings of the National Academy of Sciences 107, 9222–9227 (2010).

Wernig, M., Zhao, J.-P., Pruszak, J., Hedlund, E., Fu, D., Soldner, F., Broccoli, V., Constantine-Paton, M., Isacson, O. & Jaenisch, R. Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson's disease. Proceedings of the National Academy of Sciences 105, 5856–5861 (2008).

Leker, R. R., Soldner, F., Velasco, I., Gavin, D. K., Androutsellis-Theotokis, A. & McKay, R. D. G. Long-lasting regeneration after ischemia in the cerebral cortex. Stroke 38, 153–161 (2007).

Androutsellis-Theotokis, A., Leker, R. R., Soldner, F., Hoeppner, D. J., Ravin, R., Poser, S. W., Rueger, M. A., Bae, S.-K., Kittappa, R. & McKay, R. D. G. Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 442, 823–826 (2006).

Seyfried, J., Soldner, F., Kunz, W. S., Schulz, J. B., Klockgether, T., Kovar, K. A. & Wullner, U. Effect of 1-methyl-4-phenylpyridinium on glutathione in rat pheochromocytoma PC 12 cells. Neurochem Int. 36, 489–497 (2000).

Soldner, F., Weller, M., Haid, S., Beinroth, S., Miller, S. W., Wullner, U., Davis, R. E., Dichgans, J., Klockgether, T. & Schulz, J. B. MPP+ inhibits proliferation of PC12 cells by a p21(WAF1/Cip1)-dependent pathway and induces cell death in cells lacking p21(WAF1/Cip1). Exp Cell Res 250, 75–85 (1999).

Seyfried, J., Soldner, F., Schulz, J. B., Klockgether, T., Kovar, K. A. & Wullner, U. Differential effects of L-buthionine sulfoximine and ethacrynic acid on glutathione levels and mitochondrial function in PC12 cells. Neurosci Lett 264, 1–4 (1999).


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