Dr. Shu Chen received his Ph.D. in Biochemical Pharmacology from the State University of New York at Buffalo in 1993. He came to CWRU as a Research Associate and moved on to be an Instructor and Assistant Professor in Case's Institute of Pathology. Presently, Dr. Chen is a Professor of Pathology at the Case Western Reserve University School of Medicine.
Alzheimer's disease (AD), Parkinson's disease (PD) and prion disease are neurodegenerative diseases characterized by neuronal cell death and accumulation of insoluble protein aggregates. The central theme of my research is to elucidate the molecular pathogenesis of neurodegenerative diseases in order to develop translational approaches to early diagnosis and disease-modifying therapy. This research focus began with our earlier studies on the biochemical properties of prion “strains” in human prion diseases, leading to the new diagnostic criteria based on both the conformers and genotype of prion protein. Our research has now expanded to include molecular, genetic and translational studies of more common brain disorders, including Parkinson’s disease and Alzheimer’s disease, with the current efforts devoted to the identification of biomarker and genetic modifiers of neurodegeneration.
Biochemical, genetic, and translational studies of LRRK2 in Parkinson disease
Our research on Parkinson’s disease (PD) was inspired by the new genetic discovery in 2004 that mutations in LRRK2 (leucine-rich repeats kinase 2) are the most frequent cause of familial PD. We found that LRRK2 was localized to the Lewy bodies in many non-LRRK2 carriers of PD and dementia with Lewy bodies (Zhu et al., 2006). This was the first study implicating LRRK2 in the pathogenesis of not only familial PD, but also sporadic PD and related Parkinsonism disorders. Through detailed biochemical studies on the enzymatic activities of LRRK2, we were among the first to prove that LRRK2 is both a protein kinase and an authentic GTPase, the latter self-regulates the intrinsic kinase activity of LRRK2 (Guo et al., 2007). To elucidate the pathogenic role of LRRK2 in vivo, we have established transgenic C. elegans models of PD caused by LRRK2 clinical mutations (R1441C and G2019S) (Yao et al., 2010). We have utilized these C. elegans transgenic LRRK2 models to characterize and validate the efficacy of small molecule inhibitors of LRRK2 (Yao et al., 2013). We have also uncovered a neuroprotective role of glutaredoxin 1 in LRRK2-associated neurodegeneration, revealing a mechanism by which oxidative protein modification contribute to the pathogenesis of PD (Johnson et al., 2015; Johnson et al., 2016).
Genetic and biomarker studies of PD, AD and AD-related dementias
The Chen lab takes a collaborative and multidisciplinary approach to better understand the core mechanisms that drive neurodegeneration and to translate bench science into clinical practice. Our collaboration with the big data experts has resulted in a NIH funded multi-PI R01 award to identify new genetic and druggable targets impacting AD pathogenesis (PIs: Chen/Xu, 2018-2023). More recently, we have worked closely with basic scientists and clinical faculty in order to develop patient-oriented projects that potentially impact molecular diagnosis of PD and dementia. These include a multi-PI NIH U01 award to identify skin biomarkers for PD (PIs: Chen/Gunzler/Zou, 2019-2024), and a multi-PI NIH R01 award to develop novel biomarker assays for Lewy body dementia using peripheral specimens (PIs: Chen/Kraus, 2020-2025).
View All Publications: https://www.ncbi.nlm.nih.gov/myncbi/shu.chen.1/bibliography/public/
Gambetti P, Parchi P, Capellari S, Russo C, Tabaton M, Teller JK, Chen SG (2001). Mechanisms of phenotypic heterogeneity in prion, Alzheimer and other conformational diseases. J Alzheimers Dis. 2001 Feb;3(1):87-95. doi: 10.3233/jad-2001-3113. PMID: 12214077
Zou W, Zheng J, Gray D, Gambetti P, Chen SG (2004). Antibody to DNA detects scrapie but not normal prion protein. Proc Natl Acad Sci U S A. 2004 Feb 3;101(5):1380-5. PMCID: PMC337061
Zhu X, Babar A, Siedlak LS, Yang Q, Ito G, Iwatsubo T, Smith MA, Perry G, Chen SG (2006). LRRK2 in Parkinson’s disease and dementia with Lewy bodies. Mol Neurodegener. 2006 Nov 30;1:17. PMCID: PMC1693553
Guo L, Gandhi P, Wang W, Petersen R, Wilson-Delfosse AL, Chen SG (2007). The Parkinson's disease-associated protein, leucine-rich repeat kinase 2 (LRRK2), is an authentic GTPase that stimulates kinase activity. Exp Cell Res. 2007 Oct 1;313(16):3658-70. PMCID: PMC2083285
Yao C, El Khoury R, Wang, W, Byrd TA, Pehek EA, Thacker C, Zhu X, Smith M, Wilson-Delfosse A, Chen SG (2010). LRRK2-mediated neurodegeneration and dysfunction of dopaminergic neurons in a Caenorhabditis elegans model of Parkinson's disease. Neurobiol Dis. 2010 Oct;40(1):73-81. PMCID: PMC2926296
Yao C, Johnson WM, Gao Y, Deak M, Alessi DR, Zhu X, Mieyal JJ, Roder H, Wilson-Delfosse AL, Chen SG (2013). Kinase inhibitors arrest neurodegeneration in cell and C. elegans models of Parkinson’s disease. Hum Mol Genet. 2013 Jan 15;22(2):328-44. PMCID: PMC3526163
Johnson WM, Yao C, Siedlak SL, Wang W, Zhu X, Caldwell GA, Wilson-Delfosse AL, Mieyal JJ, Chen SG (2015). Glutaredoxin deficiency exacerbates neurodegeneration in C. elegans models of Parkinson’s disease. Hum Mol Genet. 2015 Mar 1;24(5):1322-35. PMCID: PMC4321441
Johnson WM, Golczak M, Choe K, Currran PL, Gorelenkova Miller O, Yao C, Wang W, Lin J, Milkovic NM, Ray A, Ravindranath V, Zhu X, Wilson MA, Wilson-Delfosse AL, Chen SG, Mieyal JJ. Regulation of DJ-1 by glutaredoxin 1 in vivo - implications for Parkinson's disease. Biochemistry. 2016 Aug 16;55(32):4519-32. PMCID: PMC4987251
Chen SG, Stribinskis V, Rane MJ, Demuth D, Gozal E, Roberts AM, Jagadapillai R, Liu R, Choe K, Shivakumar B, Son F, Jin S, Kerber R, Adame A, Masliah E, Friedland RP (2016). Exposure to the Functional Bacterial Amyloid Protein Curli Enhances Alpha-Synuclein Aggregation in Aged Fischer 344 Rats and Caenorhabditis elegans. Sci Rep. 2016 Oct 6;6:34477. PMCID: PMC5052651
Gunzler SA, Riley DE, Chen SG, Tatsuoka CM, Johnson WM, Mieyal JJ, Walter EM, Whitney CM, Feng IJ, Owusu-Dapaah H, Wilson-Delfosse AL (2018). Motor and non-motor features of Parkinson's disease in LRRK2 G2019S carriers versus matched controls. J Neurol Sci. 2018 May 15;388:203-207. PMCID: PMC5908224
Yan T, Wang JG, Siedlak SL, Huntley Ml, Termsarasab P, Perry G, Chen SG, Wang X (2018). Rab10 Phosphorylation is a Prominent Pathological Feature in Alzheimer's Disease. J Alzheimers Dis. 2018;63(1):157-165. PMCID: PMC6008156
Wang Z, Becker K, Donadio V, Siedlak S, Yuan J, Rezaee M, Incensi A Kuzkina A, Orrú CD, Tatsuoka C, Liguori R, Gunzler SA, Caughey B, Jimenez-Capdeville ME, Zhu X, Doppler K, Cui L, Chen SG, Ma J, Zou WQ (2020). Skin α-synuclein aggregation seeding activity as a novel biomarker for Parkinson’s disease. JAMA Neurol. 2021 Jan; 78(1): 1–11. Published online 2020 Sep 28. PMCID: PMC7522783 (Erratum in: doi: 10.1001/jamaneurol.2020.4087)
Bargar C, Wang W, Gunzler, SA, LeFevre A, Wang Z, Lerner A, Singh N, Tatsuoka C, Appleby B, Zhu X, Xu R, Haroutunian V, Zou WQ, Ma J, Chen SG. Streamlined alpha-synuclein RT-QuIC assay for various biospecimens in Parkinson’s disease and dementia with Lewy bodies. Acta Neuropathol Commun 9, 62 (2021). https://doi.org/10.1186/s40478-021-01175-w