Scherzer, Clemens - Harvard Medical School - Brigham and Women’s Hospital

个人简介

Our goal is to decipher three dimensions of the transcriptional code of Parkinson’s - transcript abundance, splice structure, and sequence - and the mechanisms by which transcriptional information is compromised and perturbs biological systems and phenotypes. While the number of human genes has shrunken to ~22,000, an ever-increasing number of >100,000 unique isoforms and non-protein coding, regulatory RNAs may account for the complexity of the human brain in health and disease. We hypothesize that genetic, epigenetic, and environmental risk factors cause disease through integrated modulation of RNA abundance, sequence, and splicing. We use massively parallel whole transcriptome sequencing, computation, molecular, and systems biology to break this RNA code and strive to rapidly translate insights into new diagnostics and medicines. This innovative approach has deciphered critical bits of transcriptional information on onset mechanism, novel therapeutic targets, and causal transcripts. It revealed that reduced expression of the bioenergetics genes controlled by a master regulator - PGC-1alpha - likely occurs during the initial stages of disease, long before the onset of symptoms, and identified a molecular switch to turn off α-synuclein, the protein that accumulates in Parkinson’s patients. Because we believe that transformative discovery requires transcending conventional research boundaries, the Scherzer laboratory is interdisciplinary, including neuroscientists, genomics, computational, as well as clinical scientists. Our longitudinal Harvard NeuroDiscovery Center Biomarker Study and Biobank of 2,000 participants serves as express lane for translating lead RNAs into biomarkers and for developing a future personalized neurology. Highthroughput drug screens are used to translate transcriptional targets into new therapies.

近期论文

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β2-Adrenoreceptor is a regulator of the α-synuclein gene driving risk of Parkinson's disease. Mittal S, Bjørnevik K, Im DS, Flierl A, Dong X, Locascio JJ, Abo KM, Long E, Jin M, Xu B, Xiang YK, Rochet JC, Engeland A, Rizzu P, Heutink P, Bartels T, Selkoe DJ, Caldarone BJ, Glicksman MA, Khurana V, Schüle B, Park DS, Riise T, Scherzer CR. Science. 2017 Sep 1;357(6354):891-898. doi: 10.1126/science.aaf3934. Parkinson's disease biomarkers: perspective from the NINDS Parkinson's Disease Biomarkers Program. Gwinn K, David KK, Swanson-Fischer C, Albin R, Hillaire-Clarke CS, Sieber BA, Lungu C, Bowman FD, Alcalay RN, Babcock D, Dawson TM, Dewey RB Jr, Foroud T, German D, Huang X, Petyuk V, Potashkin JA, Saunders-Pullman R, Sutherland M, Walt DR, West AB, Zhang J, Chen-Plotkin A, Scherzer CR, Vaillancourt DE, Rosenthal LS. Biomark Med. 2017 May;11(6):451-473. doi: 10.2217/bmm-2016-0370. Epub 2017 Jun 23. Prediction of cognition in Parkinson's disease with a clinical-genetic score: a longitudinal analysis of nine cohorts. Liu G, Locascio JJ, Corvol JC, Boot B, Liao Z, Page K, Franco D, Burke K, Jansen IE, Trisini-Lipsanopoulos A, Winder-Rhodes S, Tanner CM, Lang AE, Eberly S, Elbaz A, Brice A, Mangone G, Ravina B, Shoulson I, Cormier-Dequaire F, Heutink P, van Hilten JJ, Barker RA, Williams-Gray CH, Marinus J, Scherzer CR; HBS; CamPaIGN; PICNICS; PROPARK; PSG; DIGPD; PDBP. Lancet Neurol. 2017 Aug;16(8):620-629. doi: 10.1016/S1474-4422(17)30122-9. Epub 2017 Jun 16. Defining the contribution of neuroinflammation to Parkinson's disease in humanized immune system mice. Manocha GD, Floden AM, Puig KL, Nagamoto-Combs K, Scherzer CR, Combs CK. Mol Neurodegener. 2017 Feb 14;12(1):17. doi: 10.1186/s13024-017-0158-z. Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's. Liu G, Boot B, Locascio JJ, Jansen IE, Winder-Rhodes S, Eberly S, Elbaz A, Brice A, Ravina B, van Hilten JJ, Cormier-Dequaire F, Corvol JC, Barker RA, Heutink P, Marinus J, Williams-Gray CH, Scherzer CR; International Genetics of Parkinson Disease Progression (IGPP) Consortium. Ann Neurol. 2016 Nov;80(5):674-685. doi: 10.1002/ana.24781. Identification of genetic modifiers of age-at-onset for familial Parkinson's disease. Hill-Burns EM, Ross OA, Wissemann WT, Soto-Ortolaza AI, Zareparsi S, Siuda J, Lynch T, Wszolek ZK, Silburn PA, Mellick GD, Ritz B, Scherzer CR, Zabetian CP, Factor SA, Breheny PJ, Payami H. Hum Mol Genet. 2016 Sep 1;25(17):3849-3862. doi: 10.1093/hmg/ddw206. Epub 2016 Jul 11. Seed-competent high-molecular-weight tau species accumulates in the cerebrospinal fluid of Alzheimer's disease mouse model and human patients. Takeda S, Commins C, DeVos SL, Nobuhara CK, Wegmann S, Roe AD, Costantino I, Fan Z, Nicholls SB, Sherman AE, Trisini Lipsanopoulos AT, Scherzer CR, Carlson GA, Pitstick R, Peskind ER, Raskind MA, Li G, Montine TJ, Frosch MP, Hyman BT. Ann Neurol. 2016 Sep;80(3):355-67. doi: 10.1002/ana.24716. Epub 2016 Aug 3. A Feed-Forward Circuit of Endogenous PGC-1α and Estrogen Related Receptor α Regulates the Neuronal Electron Transport Chain. Bakshi R, Mittal S, Liao Z, Scherzer CR. Parkinsons Dis. 2016;2016:2405176. doi: 10.1155/2016/2405176. Epub 2016 Mar 3. α-Synuclein in Extracellular Vesicles: Functional Implications and Diagnostic Opportunities. Lööv C, Scherzer CR, Hyman BT, Breakefield XO, Ingelsson M. Cell Mol Neurobiol. 2016 Apr;36(3):437-48. doi: 10.1007/s10571-015-0317-0. Epub 2016 Mar 18. Review. The NINDS Parkinson's disease biomarkers program. Rosenthal LS, Drake D, Alcalay RN, Babcock D, Bowman FD, Chen-Plotkin A, Dawson TM, Dewey RB Jr, German DC, Huang X, Landin B, McAuliffe M, Petyuk VA, Scherzer CR, Hillaire-Clarke CS, Sieber BA, Sutherland M, Tarn C, West A, Vaillancourt D, Zhang J, Gwinn K; PDBP consortium. Mov Disord. 2016 Jun;31(6):915-23. doi: 10.1002/mds.26438. Epub 2015 Oct 7. Aging, the Central Nervous System, and Mobility in Older Adults: Neural Mechanisms of Mobility Impairment. Sorond FA, Cruz-Almeida Y, Clark DJ, Viswanathan A, Scherzer CR, De Jager P, Csiszar A, Laurienti PJ, Hausdorff JM, Chen WG, Ferrucci L, Rosano C, Studenski SA, Black SE, Lipsitz LA. J Gerontol A Biol Sci Med Sci. 2015 Dec;70(12):1526-32. doi: 10.1093/gerona/glv130. Epub 2015 Sep 18. Association between α-synuclein blood transcripts and early, neuroimaging-supported Parkinson's disease. Locascio JJ, Eberly S, Liao Z, Liu G, Hoesing AN, Duong K, Trisini-Lipsanopoulos A, Dhima K, Hung AY, Flaherty AW, Schwarzschild MA, Hayes MT, Wills AM, Shivraj Sohur U, Mejia NI, Selkoe DJ, Oakes D, Shoulson I, Dong X, Marek K, Zheng B, Ivinson A, Hyman BT, Growdon JH, Sudarsky LR, Schlossmacher MG, Ravina B, Scherzer CR. Brain. 2015 Sep;138(Pt 9):2659-71. doi: 10.1093/brain/awv202. Epub 2015 Jul 28.