- Molecular and cellular mechanisms of C9orf72 pathogenesis, in particular studies on synaptic dysfunction
- Development of a biomarker to monitor C9orf72 therapeutic intervention
- Development of PET ligand for EAAT2 as a biomarker for astrocyte dysfunction in ALS and other neurodegenerative diseases
The research interest of my laboratory lies in the elucidation of disease pathways for neurodegenerative disorders, including, but not exclusively, Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). Specifically, I have continued an area of investigation I have been pursuing since my doctoral studies, which is aimed at understanding the role of the synaptic structure and synaptic proteins in disease progression and neurodegeneration, with an emphasis on the regulation and dysregulation of synaptic glutamate homeostasis. With the development of innovative techniques for acquiring adult patient-derived pluripotent stem (iPS) cells, we have adopted and validated this extremely valuable human cell culture platform to better understand the human molecular and cellular aspects of disease pathways. Human culture models systems will allow us to overcome known interspecies differences, which are especially critical at the level of transcriptional regulation and RNA processing. In combination with advanced molecular and cellular technologies, our goal is to discover novel pathways that harbor potential specific drug targets for future therapeutic development.
Ongoing research in my laboratory is focused on the elucidation of the molecular mechanisms of the newly discovered gene mutation in C9orf72. This mutation is characterized by an expanded GGGGCC hexanucleotide repeat in the non-coding region of the C9orf72 gene on chromosome 9p21 and represents the most common genetic abnormality in frontotemporal dementia (FTD; 10-30%) and ALS (20-50%). Specifically, we are interested in the contribution of synaptic dysfunction to C9orf72 disease pathogenesis.
Side projects in our laboratory involve the development of two biomarker assays. One targeted at monitoring therapeutic interventions for C9orf72 and the other targeted at measuring levels of astrocytic glutamate transporter EAAT2 with the use of an EAAT2-specific PET ligand.
- Li Y, Sattler R, Yang EJ, Nunes A, Ayukawa Y, Akhtar S, Ji G, Zhang PW, Rothstein JD (2011): Harmine, a natural beta-carboline alkaloid, upregulates astroglial glutamate transporter expression. Neuropharmacology Jun 60(7-8):1168-75.
- Adamczyk A, Gause CD, Sattler R, Vidensky S, Rothstein JD, Singer H, Wang T (2011): Genetic and functional studies of a missense variant in a glutamate transporter, SLC1A3, in Tourette syndrome. Psychiatr Genet Apr; 21(2):90-7.
- Sattler R, Ayukawa Y, Coddington LT, Gutenkunst J, Michaud R, Wolfe J, Taylor R, Lin S, Chipkin R, Block D and Rothstein JD (2011): Human Nasal olfactory epithelium as a dynamic marker for CNS therapy development. Exp Neurol. Dec;232(2):203-11
- Shukla K, Thomas AG, Ferraris DV, Hin N, Sattler R, Alt J, Rojas C, Slusher BS, Tsukamoto T. (2011):Inhibition of xc- transporter-mediated cystine uptake by Sulfasalazine analogs. Bioorg Med Chem Lett. Oct 15;21(20):6184-7.
- Roybon, L., Lamas, N.J., Garcia-Diaz, A., Yang, E.J., Sattler, R., Jackson-Lewis, V., Kim, Y.A., Kachel, C.A., Rothstein, J.D., Przedborski, S., Wichterle, H., & Henderson, C.E. (2013). Human stem cell-derived spinal cord astrocytes with defined mature or reactive phenotypes. Cell Rep., 4(5), 1035-1048. PMID: 23994478
- Sattler, R*., Tyler, B., Hoover, B., Coddington, L.T., Recinos, V., Hwang, L., Brem, H., & Rothstein, J.D. (2013). Increased expression of glutamate transporter GLT-1 in peritumoral tissue associated with prolonged survival and decreases in tumor growth in a rat model of experimental malignant glioma. J Neurosurg., 119(4), 878-886. PMID: 23909244 *Corresponding author
- Donnelly, C.J., Zhang, P.W., Pham, J.T., Heusler A.R., Mistry N.A., Vidensky S., Daley E.L., Poth, E.M., Hoover B., Fines, D.M., Maragakis N., Tiernari P.J., Petrucelli L., Traynor B.J., Wang J., Rigo F., Bennett C.F., Blackshaw S., Sattler R.*, Rothstein, J.D.* (2013). RNA toxicity from the ALS/FTD C9ORF72 Expansion is mitigated by antisense intervention. Neuron 80, 415-428 *Co-corresponding senior authors
- Haeusler AR, Donnelly CJ, Periz G, Simko EAJ, Shaw PG, Maragakis NJ, Troncoso JC, Pandey A, Sattler R, Rothstein JD, Wang J (2014). C9orf72 Nucleotide Repeat Structure Initiates Molecular Cascades of Disease. Nature, Mar 5. doi: 10.1038/nature13124.
- Abazyan, S., Yang, E.U., Abazyan, B., Xia, M., Yang, C., Rojas, C., Slusher, B., Sattler, R., Pletnikov, M. (2014). Mutant Disrupted-In-Schizophrenia 1 in astrocytes: focus on glutamate metabolism. J Neurosci Res Aug 8. doi: 10.1002/jnr.23459. [Epub ahead of print]
- Mendez E. and Sattler R (2014) Biomarker development for C9orf72 repeat expansion in ALS. Special Issue: The multifaceted Nature of ALS: Discoveries and Challenges of the last 5 years. Brain Research. 2014 Sep 26. pii: S0006-8993(14)01263-3. doi: 10.1016/j.brainres.2014.09.041. [Epub ahead of print]
- Donnelly CJ, Grima JC and Sattler R (2014). Aberrant RNA homeostasis in amyotrophic lateral sclerosis: potential for new therapeutic targets? Neurodegener Dis Manag. 2014 Dec;4(6):417-437.