- Aging and Neurodegeneration

- The current projects in our laboratory will use an integrated approach (i.e., combining molecular, cellular, biochemical, genetic and physiological techniques) by constructing in vitro and in vivo models to address the following critical issues:

(1) How does aging and disease-causing mutations provoke neurodegeneration?

(2) Why specific neuron types are more susceptible to these disease-causing mutations.

(3) How do different cell types, such as astrocytes and oligodendrocytes, contribute to disease progression?

Specifically, we will utilize different sets of transgenic mice expressing wild type and disease-linked mutations in human TDP-43, FUS/TLS and C9ORF72, including a novel model in which mouse TDP-43 is replaced with human gene. Furthermore, we will gain insight into molecular and cellular signatures of ALS-linked mutations in TDP-43, FUS/TLS and C9ORF72 with a genome-wide unbiased and quantitative approach to identify the protein and RNA interactors for these proteins.

1. Lai S. L., Ling, S.-C., Kuo, L. H., Shu, Y. C., Chow, W. Y. and Chang, Y. C., “Characterization of granular particles isolated from postsynaptic densities” J. Neurochem. 1998: 1694-1701

2. Angenstein F., Evans A. M., Settlage R. E., Moran S. T., Ling S.-C., Klintsova A. Y., Shabanowitz J., Hunt D. F., Greenough W. T., “A receptor for activated C kinase is part of messenger ribonucleoprotein complexes associated with polyA-mRNAs in neurons” J. Neurosci. 2002: 8827-37.

3. Ling S.-C., Fahrner P. S., Greenough W. T., Gelfand V. I. “Transport of Drosophila fragile X mental retardation protein-containing ribonucleoprotein granules by kinesin-1 and cytoplasmic dynein” Proc Natl Acad Sci U S A. 2004 :17428-17433

4. Angenstein F., Evans A. M., Ling S.-C., Settlage R. E., Ficarro S., Carrero-Martinez F. A., Shabanowitz J., Hunt D. F., Greenough W. T. “Proteomic characterization of mRNP-complexes bound to nontranslated or translated polyA-mRNAs in the rat cerebral cortex” J. Biol. Chem. 2005: 6496-6503

5. Kim H., Ling S.-C., Rogers G. C., Kural C., Selvin P., Rogers S. L., and Gelfand V. I., “Microtubule binding by dynactin is required for microtubule organization but not cargo transport.”. J. Cell Biol. 2007: 641-651

6. Ling S.-C., Albuquerque, C., Han, J.-S., Lagier-Tourenne, C., Tokunaga, S., Zhou, H., Cleveland, D. W., “ALS-associated mutations in TDP-43 increase its stability and promote TDP-43 complexes with FUS/TLS.” Proc Natl Acad Sci U S A., 2010: 13318-13323

7. Polymenidou M., Lagier-Tourenne C., Hutt K. R., Huelga S. C., Moran J., Liang T. Y., Ling S.-C., Sun E., Wancewicz E., Mazur C., Kordasiewicz, H., Sedaghat Y., Donohue J. P., Shiu L., Bennett C. F., Yeo G. W., Cleveland D. W., “Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43.” Nature Neurosci., 2011: 459-468.

8. Lagier-Tourenne, C., Polymenidou, M., Hutt, K. R., Vu, A. Q., Clutario, K., Baughn, M., Huelga, S. C., Ling, S.-C., Liang, T. Y., Mazur, C. Wancewicz, E., Watt, A., Freier, S., Hicks, G. G., Donohue, J. P., Shiue, L., Bennett, C. F., Ravits, J., Cleveland, D. W., and Yeo, G. W., “Convergent roles of FUS/TLS and TDP-43 in processing RNAs with long introns.” Nature Neurosci. 2012: 1488-1497

9. Arnold, E.*, Ling, S.-C*., Lagier-Tourenne C., Polymenidou M., Huelga S., Ditsworth, D., Kordasiewicz, H. B., McAlonis-Downes, M., Platoshyn, O., Parone, P., Da Cruz, S., Swing, D. Tessarollo, L., Marsala, M., Shaw, C. E., Yeo, Y., Cleveland, D. W., “ALS-linked TDP-43 mutantions produce aberrant RNA splicing and adult-onset motor disease without aggregation or loss of nuclear TDP-43.” Proc Natl Acad Sci U S A, 2013: E736-745. * co-first author

10. Ling, S.-C., Polymenidou M., and Cleveland, D. W., “Converging mechanisms in ALS and FTLD: disrupted RNA or protein homeostasis.” Neuron, 2013: 416-438.