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Tim Bartels, PhD
Assistant Scientist, Brigham and Women's Hospital
Assistant Professor of Neurology, Harvard Medical School

Brigham and Women's Hospital
Department of Neurology
75 Francis Street
Boston, MA 02115


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Research Narrative:

Already during my PhD thesis I became interested in the cellular and molecular mechanisms underlying Parkinson’s Disease (PD). Despite advances in symptomatic treatments of PD in the last decades, the underlying mechanisms causing neurodegeneration is still poorly understood.

I am particularly interested in the role of alpha-synuclein (aSyn), a neuronal protein of unknown physiological function whose misfolding shows a strong link to disease progression.

Intraneuronal aggregates of aSyn (i.e., Lewy bodies and neurites) are the pathological hallmark of Parkinson’s disease (PD). Moreover, genetic increases in aSyn expression and point mutations in the aSyn gene are an increasingly well-documented precipitant of early onset familial PD (fPD). Our lab recently discovered that aSyn, normally exists in cells and brain tissue principally as an alpha-helically folded tetramer with resistance to aggregation, whereas all prior studies had described the protein as a ‘natively unfolded’ monomer that can rapidly aggregate into abnormal beta-sheet-rich oligomers. Based on our unexpected finding, I am currently working on identifying cellular factors which could trigger the depolymerization of physiologically folded aSyn tetramers and allow the free monomer to aggregate abnormally in neurons and to shed light on the physiological folding mechanism of aSyn. Our hypothesis is that, analogous to transthyretin-based amyloidosis (which causes familial cardiac amyloidosis and familial amyloidotic polyneuropathy), a tetramer-destabilization event which leads to partially unfolded monomeric αSyn precedes the initiation of pathological aggregation. Another main focus of my work is to develop an assay to detect changes in conformation of the soluble pool of aSyn in biological fluids (blood, CSF, ISF) in a hope to find an early biomarker of disease progression

 

 


Education:
PhD

Publications (Pulled from Harvard Catalyst Profiles):

1. Bartels T. A traffic jam leads to Lewy bodies. Nat Neurosci. 2019 07; 22(7):1043-1045.

2. Rovere M, Powers AE, Jiang H, Pitino JC, Fonseca-Ornelas L, Patel DS, Achille A, Langen R, Varkey J, Bartels T. E46K-like a-synuclein mutants increase lipid interactions and disrupt membrane selectivity. J Biol Chem. 2019 Jun 21; 294(25):9799-9812.

3. Rovere M, Powers AE, Patel DS, Bartels T. pTSara-NatB, an improved N-terminal acetylation system for recombinant protein expression in E. coli. PLoS One. 2018; 13(7):e0198715.

4. Rovere M, Sanderson JB, Fonseca-Ornelas L, Patel DS, Bartels T. Refolding of helical soluble a-synuclein through transient interaction with lipid interfaces. FEBS Lett. 2018 05; 592(9):1464-1472.

5. Schapansky J, Khasnavis S, DeAndrade MP, Nardozzi JD, Falkson SR, Boyd JD, Sanderson JB, Bartels T, Melrose HL, LaVoie MJ. Familial knockin mutation of LRRK2 causes lysosomal dysfunction and accumulation of endogenous insoluble a-synuclein in neurons. Neurobiol Dis. 2018 03; 111:26-35.

6. Dettmer U, Ramalingam N, von Saucken VE, Kim TE, Newman AJ, Terry-Kantor E, Nuber S, Ericsson M, Fanning S, Bartels T, Lindquist S, Levy OA, Selkoe D. Loss of native a-synuclein multimerization by strategically mutating its amphipathic helix causes abnormal vesicle interactions in neuronal cells. Hum Mol Genet. 2017 09 15; 26(18):3466-3481.

7. 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. ß2-Adrenoreceptor is a regulator of the a-synuclein gene driving risk of Parkinson's disease. Science. 2017 09 01; 357(6354):891-898.

8. Bartels T. Conformation-Specific Detection of a-Synuclein: The Search for a Biomarker in Parkinson Disease. JAMA Neurol. 2017 02 01; 74(2):146-147.

9. Dettmer U, Selkoe D, Bartels T. New insights into cellular a-synuclein homeostasis in health and disease. Curr Opin Neurobiol. 2016 Feb; 36:15-22.

10. Dettmer U, Newman AJ, Soldner F, Luth ES, Kim NC, von Saucken VE, Sanderson JB, Jaenisch R, Bartels T, Selkoe D. Corrigendum: Parkinson-causing a-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation. Nat Commun. 2015 Jul 30; 6:8008.