HiF-Seq™ platform enables high efficiency single cell sequencing and is particularly well-suited for frozen tissue sections from post-mortem brain tissue which have been challenging for conventional single cell sequencing technologies.

Using this proprietary technology, we are creating the world’s largest repository of data from high-quality, clinically characterized brain tissues of patients with neurodegenerative diseases including Alzheimer’s and Parkinson’s. With this approach, we can study  genomic information for individual cells.

In parallel, we are developing diagnostic assays for known targets in recognized neurodegenerative pathways, as well as novel targets that have to date been challenging to detect and quantitate as biomarkers.

As the repository of data derived from the HiF-snRNAseq™ platform continues to grow, it will be increasingly valuable for guiding development of diagnostic assays and therapeutics .

 

Elucidating critical disease pathways, biomarkers and targets with unprecedented resolution to inform development of new therapeutics and diagnostics.

 

HiF-Seq™ Platform

 

Analysis

 

Developing Diagnostic Assays

Biomarker targets of c-Abl pathway: Activated c-Abl and its downstream targets contribute to the pathogenesis of Parkinson’s disease (PD) by driving cytotoxicity and subsequent neurodegeneration. We are developing ultra-sensitive liquid biopsy-based diagnostic assays targeting the c-Abl pathway.

RIPK2 and pS176-RIPK2 are two potential biomarker candidates for Parkinson’s and related neurodegenerative diseases: RIPK2 activation plays a central role in microglia-mediated neuroinflammation and A1 astrocyte conversion which are thought to mediate neurodegeneration in PD, Alzheimer’s disease (AD) and other neurodegenerative disorders. We are developing diagnostics for RIPK2 and activated RIPK2 as potential markers for these conditions.

 
 

Mandir, A.S., S. Przedborski, V. Jackson-Lewis, Z.-Q. Wang, C. M. Simbulan-Rosenthal, M. E. Smulson, B.E. Hoffman, D. B. Guastella, V.L. Dawson and T.M. Dawson.  “Poly (ADP-Ribose) Polymerase Activation Mediates MPTP-Induced Parkinsonism.”  Proc. Natl. Acad. Sci., U.S.A. 96: 5774-5779 (1999), PMID: 10318960, PMCID: PMC21936.

  

Ko, H.S., R. von Coelln, S. R. Sriram, S.W. Kim, K.K.K. Chung, B. Johnson, O. Pletnikova, E.L. Goh, H. Song, B.J. Park, M.J. Kim, S.H. Kim, V.L. Dawson, and T.M. Dawson. “Accumulation of the Authentic Parkin Substrate, Aminoacyl-tRNA Synthetase Cofactor, p38/JTV-1, Leads to Catecholaminergic Cell Death”  J. Neurosci., 25:7968-7978 (2005), PMID: 16135753, PMCID: PMC6725452.

 

Ko, H.S., Y. Lee, J.-H. Shin, S.S. Karuppagounder, B.S. Gadad, A.J. Koleske, O. Pletnikova, J.C. Troncoso, V.L. Dawson*, T.M. Dawson. Phosphorylation by the c-Abl Protein Tyrosine Kinase Inhibits Parkin’s Ubiquitination and Protective Function.” Proc. Natl. Acad. Sci. U.S.A., published ahead of print September 7, 2010, doi:10.1073/pnas.1006083107; 107:16691-16696 (2010) PMID: 20823226, PMCID: PMC2944759.

Shin, J.-H., H.S. Ko, H.C. Kang, Y. Lee, Y.-I. Lee, O. Pletinkova, J.C. Troncoso, V.L. Dawson* and T.M. Dawso*. “PARIS (ZNF746) Repression of PGC-1α Contributes to Neurodegeneration in Parkinson’s Disease.” Cell, 144:689-702 (2011), PMID: 21376232, PMCID: PMC3063894.

 

Lee, Y., S.S. Karuppagounder, J.-H. Shin, Y.-I. Lee. H.S. Ko, D. Swing, B.D. Lee. H.C. Kang, L. Tessarollo, V.L. Dawson and T.M. Dawson, “Parthanatos Mediates AIMP2 Activated Age Dependent Dopaminergic Neuronal Loss.” Nature Neuroscience, 16:1392-1400 (2013). PMID: 23974709, PMCID: PMC3785563.

  

Brahmachari, S., P.Ge, S.H. Lee, D. Kim, S.S. Karuppagounder, M. Kumar, X. Mao, Y. Lee, O. Pletnikova, J.C. Troncoso, V.L. Dawson, T.M.Dawson and H.S. Ko. “Activation of tyrosine kinase c-Abl contributes to a-Synuclein-Induced Neurodegeneration.” J. Clinical Investigation, 26:2970-2988.  doi: 10.1172/JCI85456. (2016). PMID: 27348587, PMCID: PMC4966315.

 

Lee, Y., D. Stevens, S.-U. Kang, H. Jiang, Y.-I. Lee, H.S. Ko, L.A. Scarffe, G.E. Umanah, H. Kang, T.I. Kam, K. Allen, S. Brahmachari, J.W. Kim, S. Neifert, S.P. Yun, F.C. Fiesel, W. Springer, V.L. Dawson,  J.-H. Shin and T.M. Dawson. “PINK1 Primes Parkin-mediated ubiquitination of PARIS in dopaminergic survival,” Cell Reports, 18:918-932 (2017) DOI: 10.1016/j.celrep.2016.12.090 (2017). PMID: 28122242, PMCID: PMC5312976.

 

Kam, T.-I., X. Mao, H. Park, S.S. Karuppagounder, S.-C. Chou, G.E. Umanah, S. Brahmachari, S.P. Yun, N. Panicker, R. Chen, S.A. Andrabi, C. Qi, G.G. Poirier, O. Pletnikova, J.C. Troncoso, L.M. Bekris, J.B. Leverenz, A.Pantelyat, H.S. Ko, L.S. Rosenthal, T.M. Dawson and V.L. Dawson “Poly (ADP-ribose) Drives Pathologic a-Synuclein Neurodegeneration.” *Both authors contributed equally, Science 362, eaat8407 (2018). DOI: 10.1126/science.aat8407, PMID: 30385548, PMCID: PMC6431793.

 

Brahmachari, S., C. Yuan, S.S. Karuppagounder, P.Ge, D. Kim, A. Liu, H. Jiang, X. Mao, Y. Lee, D.A. Swing, L. Tessarollo, H.S. Ko, V.L. Dawson and T.M. Dawson. “Parkin interacting substrate zinc finger protein 746 is a pathologic mediator in Parkinson’s disease, Brain, 142:2380-2401 (2019) DOI: 10.1093/brain/awz172 PMID: 31237944, PMCID: PMC6658849.

Pirooznia, S.K., C. Yuan, M. Khan, S.S. Karuppagounder, L. Wang, Y. Xiong, S.U. Kang, Y. Lee, V.L. Dawson and T.M. Dawson. “PARIS induced defects in mitochondrial biogenesis drives dopamine neuron loss under conditions of Parkin or PINK1 deficiency.” Molecular Neurodegneration, Mar 5;15(1):17. doi: 10.1186/s13024-020-00363-x. PMID: 32138754