Positions

Overview

  • Dr. Chen is a neuroscientist whose research is focused on neurodegenerative diseases including prion disease, Alzheimer's disease, Lewy body dementia, and Parkinson's disease. He received his Ph.D. in biochemical pharmacology from the State University of New York at Buffalo in 1993. Before coming to UAB in 2021, he was a Professor of Pathology at the Case Western Reserve University School of Medicine.

    Dr. Chen's laboratory investigates pathogenic mechanisms underlying neurodegenerative diseases characterized by protein misfolding and accumulation of insoluble amyloidogenic aggregates. The central theme of his 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.

    • Selected Publications

    Academic Article

    Year Title Altmetric
    2022 Potential long-term effect of tumor necrosis factor inhibitors on dementia risk: A propensity score matched retrospective cohort study in US veterans..  Alzheimer's and Dementia.  18:1248-1259. 2022
    2021 Diagnostic value of skin RT-QuIC in Parkinson’s disease: a two-laboratory study.  npj Parkinson's Disease.  7. 2021
    2021 Discrimination of MSA-P and MSA-C by RT-QuIC analysis of olfactory mucosa: the first assessment of assay reproducibility between two specialized laboratories.  Molecular Neurodegeneration.  16. 2021
    2021 Streamlined alpha-synuclein RT-QuIC assay for various biospecimens in Parkinson’s disease and dementia with Lewy bodies.  Acta Neuropathologica Communications.  9. 2021
    2021 Gut-microbiota-microglia-brain interactions in Alzheimer's disease: knowledge-based, multi-dimensional characterization..  Alzheimer's Research and Therapy.  13:177. 2021
    2021 Skin α-Synuclein Aggregation Seeding Activity as a Novel Biomarker for Parkinson Disease.  JAMA Neurology.  78:30-40. 2021
    2019 Vitamin B 12 modulates Parkinson’s disease LRRK2 kinase activity through allosteric regulation and confers neuroprotection.  Cell Research.  29:313-329. 2019
    2018 Motor and non-motor features of Parkinson's disease in LRRK2 G2019S carriers versus matched controls.  Journal of the Neurological Sciences.  388:203-207. 2018
    2018 Rab10 Phosphorylation is a Prominent Pathological Feature in Alzheimer's Disease.  Journal of Alzheimer's Disease.  63:157-165. 2018
    2017 Novel strain properties distinguishing sporadic prion diseases sharing prion protein genotype and prion type.  Scientific Reports.  7. 2017
    2016 Exposure to the Functional Bacterial Amyloid Protein Curli Enhances Alpha-Synuclein Aggregation in Aged Fischer 344 Rats and Caenorhabditis elegans.  Scientific Reports.  6. 2016
    2016 Regulation of DJ-1 by Glutaredoxin 1 in Vivo: Implications for Parkinson's Disease.  Biochemistry.  55:4519-4532. 2016
    2015 Prion protein functions as a ferrireductase partner for ZIP14 and DMT1.  Free Radical Biology and Medicine.  84:322-330. 2015
    2015 Glutaredoxin deficiency exacerbates neurodegeneration in C. Elegans models of Parkinson's disease.  Human Molecular Genetics.  24:1322-1335. 2015
    2015 The roles of redox enzymes in Parkinson's disease: Focus on glutaredoxin. 2015
    2013 Kinase inhibitors arrest neurodegeneration in cell and C. elegans models of LRRK2 toxicity.  Human Molecular Genetics.  22:328-344. 2013
    2012 LRRK2 regulates mitochondrial dynamics and function through direct interaction with DLP1.  Human Molecular Genetics.  21:1931-1944. 2012
    2012 Assessing prion infectivity of human urine in sporadic Creutzfeldt-Jakob disease 2012
    2012 LRRK2 Directly Interacts with DLP1 to Regulate Mitochondrial Dynamics and Function.  Microscopy and Microanalysis.  18:196-197. 2012
    2011 Selection and characterization of DNA aptamers against PrPSc.  Experimental Biology and Medicine.  236:466-476. 2011
    2011 CD3 in Lewy pathology: Does the abnormal recall of neurodevelopmental processes underlie Parkinson's disease.  Journal of Neural Transmission.  118:23-26. 2011
    2010 Characterization of the prion protein in human urine.  Journal of Biological Chemistry.  285:30489-30495. 2010
    2010 LRRK2-mediated neurodegeneration and dysfunction of dopaminergic neurons in a Caenorhabditis elegans model of Parkinson's disease.  Neurobiology of Disease.  40:73-81. 2010
    2010 Paradoxical role of prion protein aggregates in redox-lron induced toxicity.  PLoS One.  5. 2010
    2010 Divalent metal transporter, iron, and Parkinson's disease: A pathological relationship.  Cell Research.  20:397-399. 2010
    2010 Penicillin sulfone inhibitors of class D β-lactamases.  Antimicrobial Agents and Chemotherapy.  54:1414-1424. 2010
    2009 Ectopic localization of FOXO3a protein in Lewy bodies in Lewy body dementia and Parkinson's disease.  Molecular Neurodegeneration.  4. 2009
    2009 Leucine-rich repeat kinase 2 (LRRK2): A key player in the pathogenesis of Parkinson's disease.  Journal of Neuroscience Research.  87:1283-1295. 2009
    2009 Neuronal mitochondrial amelioration by feeding acetyl-L-carnitine and lipoic acid to aged rats.  Journal of Cellular and Molecular Medicine.  13:320-333. 2009
    2009 Cryptic peptides of the kringle domains preferentially bind to disease-associated prion protein.  Journal of Alzheimer's Disease.  16:421-431. 2009
    2008 The Roc domain of leucine-rich repeat kinase 2 is sufficient for interaction with microtubules.  Journal of Neuroscience Research.  86:1711-1720. 2008
    2008 Leucine-rich repeat kinase 2 colocalizes with α-synuclein in Parkinson's disease, but not tau-containing deposits in tauopathies.  Neurodegenerative Diseases.  5:222-224. 2008
    2007 The Parkinson's disease-associated protein, leucine-rich repeat kinase 2 (LRRK2), is an authentic GTPase thatstimulates kinase activity.  Experimental Cell Research.  313:3658-3670. 2007
    2007 FadA from Fusobacterium nucleatum utilizes both secreted and nonsecreted forms for functional oligomerization for attachment and invasion of host cells.  Journal of Biological Chemistry.  282:25000-25009. 2007
    2007 Inducible overexpression of wild-type prion protein in the muscles leads to a primary myopathy in transgenic mice 2007
    2006 LRRK2 in Parkinson's disease and dementia with Lewy bodies.  Molecular Neurodegeneration.  1. 2006
    2006 Overexpression of GRK2 in Alzheimer disease and in a chronic hypoperfusion rat model is an early marker of brain mitochondrial lesions.  Neurotoxicity Research.  10:43-56. 2006
    2006 LRRK2 protein is a component of Lewy bodies [3].  Annals of Neurology.  60:617-618. 2006
    2006 Gerstmann-Sträussler-Scheinker: A new phenotype with 'curly' PrP deposits.  Journal of Neuropathology and Experimental Neurology.  65:642-651. 2006
    2006 Leucine-rich repeat kinase 2: Relevance to Parkinson's disease 2006
    2006 Advances in Prion Disease Surveillance.  Advances in Clinical Chemistry.  41:263-292. 2006
    2006 Erratum: DNA aptamers that bind to PrPC and not PrPSc show sequence and structure specificity (Experimental Biology and Medicine (2006) 231 (204-214)).  Experimental Biology and Medicine.  231:485. 2006
    2006 Chronic wasting disease of elk and deer and Creutzfeldt-Jakob disease: Comparative analysis of the scrapie prion protein.  Journal of Biological Chemistry.  281:4199-4206. 2006
    2006 DNA aptamers that bind to PrPC and not PrPSc show sequence and structure specificity.  Experimental Biology and Medicine.  231:204-214. 2006
    2006 Fusion of Doppel to octapeptide repeat and N-terminal half of hydrophobic region of prion protein confers resistance to serum deprivation.  Microbiology and Immunology.  50:203-209. 2006
    2005 Chronic wasting disease of elk: Transmissibility to humans examined by transgenic mouse models 2005
    2005 Mitochondria DNA deletions in atherosclerotic hypoperfused brain microvessels as a primary target for the development of Alzheimer's disease.  Journal of the Neurological Sciences.  229-230:285-292. 2005
    2005 Creutzfeldt-Jakob disease (CJD) with a mutation at codon 148 of prion protein gene: Relationship with sporadic CJD.  American Journal of Pathology.  167:1729-1738. 2005
    2005 Sensitive detection of prion protein in human urine.  Experimental Biology and Medicine.  230:343-349. 2005
    2004 Protease-resistant human prion protein and ferritin are cotransported across Caco-2 epithelial cells: Implications for species barrier in prion uptake from the intestine 2004
    2004 Sensitivity of 14-3-3 protein test varies in subtypes of sporadic Creutzfeldt-Jakob disease.  Neurology.  63:436-442. 2004
    2004 Is nitric oxide a key target in the pathogenesis of brain lesions during the development of Alzheimer's disease?.  Neurological Research.  26:547-553. 2004
    2004 Antibody to DNA detects scrapie but not normal prion protein 2004
    2004 Copper Mediates Dityrosine Cross-Linking of Alzheimer's Amyloid-β.  Biochemistry.  43:560-568. 2004
    2003 Identification of Novel Proteinase K-resistant C-terminal Fragments of PrP in Creutzfeldt-Jakob Disease.  Journal of Biological Chemistry.  278:40429-40436. 2003
    2003 Sporadic and familial CJD: Classification and characterisation.  British Medical Bulletin.  66:213-239. 2003
    2003 Hereditary Creutzfeldt-Jakob disease and fatal familial insomnia.  Clinics in Laboratory Medicine.  23:43-64. 2003
    2003 Characterization of prion proteins..  Methods in Molecular Biology.  217:305-314. 2003
    2002 A journey through the species barrier.  Neuron.  34:854-856. 2002
    2002 Alteration of substrate selectivity through mutation of two arginine residues in the binding site of amadoriase II from Aspergillus sp..  Biochemistry.  41:4453-4458. 2002
    2002 Insomnia associated with thalamic involvement in E200K Creutzfeldt-Jakob disease.  Neurology.  58:362-367. 2002
    2001 Aberrant metal binding by prion protein in human prion disease.  Journal of Neurochemistry.  78:1400-1408. 2001
    2001 Novel Differences between Two Human Prion Strains Revealed by Two-dimensional Gel Electrophoresis.  Journal of Biological Chemistry.  276:37284-37288. 2001
    2001 Absence of protease-resistant prion protein in the cerebrospinal fluid of Creutzfeldt-Jakob disease 2001
    2001 Induction of HO-1 and NOS in doppel-expressing mice devoid of PrP: Implications for doppel function.  Molecular and Cellular Neuroscience.  17:768-775. 2001
    2001 Mechanisms of phenotypic heterogeneity in prion, Alzheimer and other conformational diseases.  Journal of Alzheimer's Disease.  3:87-95. 2001
    2001 Molecular profiling of paired helical filaments.  Journal of Alzheimer's Disease.  3:467-469. 2001
    2001 PrPSc typing by N-terminal sequencing and mass spectrometry.  Archives of virology. Supplementum.  209-216. 2001
    2000 38. Prion diseases including bovine spongiform encephalopathy (mad cow disease).  Facts, Research and Intervention in Geriatrics.  2000:491-502. 2000
    2000 Expression and structural characterization of the recombinant human doppel protein.  Biochemistry.  39:13575-13583. 2000
    2000 Genetic influence on the structural variations of the abnormal prion protein 2000
    2000 Cloning of amadoriase I isoenzyme from Aspergillus sp.: Evidence of FAD covalently linked to Cys342.  Biochemistry.  39:1515-1521. 2000
    2000 Aggregation and fibrillization of the recombinant human prion protein huPrP90-231.  Biochemistry.  39:424-431. 2000
    1999 Tau gene mutation in familial progressive subcortical gliosis.  Nature Medicine.  5:454-457. 1999
    1998 Opposite roles of apolipoprotein E in normal brains and in Alzheimer's disease 1998
    1998 Different patterns of truncated prion protein fragments correlate with distinct phenotypes in P102L Gerstmann-Sträussler-Scheinker disease 1998
    1998 Molecular pathology of fatal familial insomnia.  Brain Pathology.  8:539-548. 1998
    1997 Prion protein aggregation reverted by low temperature in transfected cells carrying a prion protein gene mutation.  Journal of Biological Chemistry.  272:28461-28470. 1997
    1997 Allelic origin of the abnormal prion protein isoform in familial prion diseases.  Nature Medicine.  3:1009-1015. 1997
    1997 Molecular assessment of the potential transmissibilities of BSE and scrapie to humans.  Nature.  388:285-288. 1997
    1997 Typing prion isoforms [5].  Nature.  386:232-234. 1997
    1996 Molecular basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease.  Annals of Neurology.  39:767-778. 1996
    1995 PROTEASE-RESISTANT PRION PROTEIN IN SPORADIC CREUTZFELDT-JAKOB DISEASE (CJD).  Journal of Neuropathology and Experimental Neurology.  54:416. 1995
    1995 Familial progressive subcortical gliosis: Presence of prions and linkage to chromosome 17.  Neurology.  45:1062-1067. 1995
    1995 Fatal Familial Insomnia and Familial Creutzfeldt‐Jakob Disease: Clinical, Pathological and Molecular Features.  Brain Pathology.  5:43-51. 1995
    1995 Regional distribution of protease‐resistant prion protein in fatal familial insomnia.  Annals of Neurology.  38:21-29. 1995
    1995 Synergistic activation by cis-fatty acid and diacylglycerol of protein kinase C and protein phosphorylation in hippocampal slices.  Neuroscience.  68:1017-1026. 1995
    1995 Truncated forms of the human prion protein in normal brain and in prion diseases.  Journal of Biological Chemistry.  270:19173-19180. 1995
    1994 Fatal familial insomnia and familial Creutzfeldt-Jakob disease: Different prion proteins determined by a DNA polymorphism 1994
    1994 Effects of cis-fatty acid on protein kinase C activation and protein phosphorylation in the hippocampus.  Journal of pharmaceutical science and technology : the official journal of PDA.  48:71-75. 1994
    1993 Inhibition of brain protein kinase C subtypes by lead..  Journal of Pharmacology and Experimental Therapeutics.  264:757-761. 1993
    1992 Phosphatidylcholine-dependent protein kinase C activation. Effects of cis-fatty acid and diacylglycerol on synergism, autophosphorylation and Ca2+-dependency.  Biochemical Journal.  284:221-226. 1992
    1992 Synergistic activation of type III protein kinase C by cis-fatty acid and diacylglycerol.  Biochemical Journal.  282:33-39. 1992

    Research Overview

  • 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 showed 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. 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, AD, and AD-related dementias. These translational projects are currently supported by NIH multi-PI grant awards including a U01 award to identify skin biomarkers for PD, a R01 award to develop novel biomarker assays for Lewy body dementia using peripheral tissue biopsies from the skin, olfactory mucosa, and colon, and a R01 award to translate skin biomarker assays into novel diagnostic platforms for AD and other tauopathies.

    • Full Name

  • Shu Chen