XClose

UK Dementia Research Institute at UCL

Home
Menu

Dr Tim Bartels

Programme lead: “Structure-function relationship in neurodegeneration”

Research summary

Aggregates of alpha-synuclein (αSyn) (Lewy bodies and neurites) are a pathological hallmark of Dementia with Lewy Bodies (DLB), Parkinson’s disease (PD) and Multiple System Atrophy

Dr Tim Bartels
. We recently discovered that αSyn, a neuronal protein of unclear physiological function, normally exists in cells and brain tissue principally as a α-helically folded tetramer that resists pathological aggregation. New preliminary experiments indicate that the tetrameric form is not only resistant to time-dependent self-aggregation but also shows increased resistance (compared to unfolded monomers) to misfolding initiated by tiny amounts of fibrillar material, i.e., “seeded aggregation”. Based on our new findings, it is important to identify factors that could trigger the denaturation of folded αSyn and allow its abnormal aggregation in neurons. We have found, using transient lipid contact as a catalyst for multimer formation, that lipid vesicles might act as a “liposomal chaperone” capable of conferring aggregation resistance to the large cytosolic pool of αSyn.  Furthermore, recent publications imply membranous compartments as the nucleation cores of Lewy bodies and that lipid binding is necessary for pathological oligomers to exert toxicity, showing that the αSyn-lipid interaction is central for both its physiology and pathomechanism. We are currently pursuing three major directions:

1. Elucidate the cellular mechanism of tetramer assembly, i.e., monomer conversion, through the study of soluble and membrane bound forms of physiological αSyn and determine how tetrameric αSyn is compromised by factors associated with increased risk for synucleinopathies in model systems and human tissue with a special emphasis on the involvement of lipids.

2. Diagnostically validate the shift in the αSyn tetramer/monomer ratio and the equilibrium between pathological and physiological species as an early precipitant of disease.

3. Determine the structural features and bioactivity of soluble fibrillar species of αSyn isolated from human brain of patients with DLB, PD and MSA.

We have currently openings for post-doctoral researchers and graduate students. If you are interested in doing research on problems related to alpha-synuclein and protein-lipid interaction using a variety of biophysical, biochemical, molecular biology or in vivo techniques, please send me an email at tbartels@bwh.harvard.edu to discuss possible opportunities.


Teaching summary

Dr. Tim Bartels enjoyed doing research in different environments, interacting with students of diverse backgrounds (physicists, chemists, biologists and pre-med). In addition, the biochemistry classes Dr. Bartels was excited to teach to medical students in Munich at that time underscored how helping others understand the basics of biochemistry could shape his own research direction. Dr. Bartels taught classes about neurodegenerative diseases on special topics at Brandeis University and Harvard Medical School. He has been working with a number of undergrad students, teaching them applied science at the bench during my time as a postdoc and instructor, and has also been able to motivate students who work in his lab to delve more deeply into biomedical research, with numerous students having rejoined his lab after graduation and two having finished their Master’s Thesis under his official supervision.


Education

Technical University Munich / MSc (Chemistry) / 2004

Ludwig-Maximilian University / PhD (Biophysics) / 2008

University of Arizona / Postdoctoral training (Biophysics) / 2008-2009

Harvard Medical School  Brigham / Postdoctoral training (Molecular Biology) / 2009-2011


Biography

Dr. Tim Bartels is currently leading the program “Structure-Function Relationship in Neurodegeneration” at the Dementia Research Institute at the University College London in addition to his position as an Assistant Professor of Neurology at Brigham & Women’s Hospital and Harvard Medical School. He received his Master’s Degree in Chemistry at the Technical University Munich and conducted his PhD in Biophysics at the Adolf Butenandt Institute (Director Christian Haass) at the Ludwig-Maximilian University under the official supervision of Prof. Johannes Buchner (Technical University Munich). He continued his post-doctoral training with Dennis Selkoe at Brigham & Women’s Hospital and Harvard Medical School where he also accepted his first faculty position as Instructor and later Assistant Professor of Neurology. His lab is dedicated to the involvement of the different forms of the presynaptic protein alpha-synuclein in Parkinson’s Disease and Dementia with Lewy Bodies. Furthermore, is his lab interested in novel context specific pathways of protein folding/misfolding and the involvement of lipids in neurodegeneration.   


Vision for UK DRI programme

My goal is to understand the folding mechanisms of so-called “intrinsically disordered” proteins in vivo. These proteins are characterized by domains predicted to be largely structure-less, yet they are common in eukaryotic organisms (27–41%), leading to a puzzling disconnect in the protein structure = function paradigm. My focus has been on the structures of α-Synuclein (αSyn), a protein previously believed to be “natively unfolded” that is involved in the pathogenesis of Parkinson’s disease (PD), as well as Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA), so-called “synucleinopathies”. To study the structure of αSyn, I broke the usual paradigm of doing structural analysis in recombinant systems and isolated αSyn under non-denaturing conditions from human tissue. I demonstrated that this previously labelled “natively unfolded” protein exists in a highly structured tetramer that is resistant to disease-associated misfolding, meaning that destabilizing this tetramer is an early requirement of pathogenesis in neurodegeneration. These findings forced a re-evaluation of 15 years of previous work on αSyn, opening new avenues for therapeutics and biomarkers for the treatment of PD that I am actively exploring under a filed patent.

Furthermore, αSyn is one of the most prevalent examples for “intrinsically disordered” proteins (IDPs). Since we were able to demonstrate that context specific structure formation is highly relevant for synucleinopathies, my lab has started elucidating diverse context-dependent mechanisms for IDPs that are leading to functional structures in living cells but not in the classical in vitro systems where important cellular components are missing. This has the potential to provide insight into the basic biology of this interesting class of proteins, many with a strong connection to neurodegeneration (e.g., TDP-43, PrP, Tau). I believe that in these proteins, pathways driven by kinetics, not necessarily thermodynamic stability, are important for what functional and pathogenic forms are present in a living cell. Therefore, understanding these pathways will ultimately be key to understand the molecular mechanisms of the neurodegenerative diseases associated with these proteins.

Publications
  1. Rovere, M., Powers, A. E., Patel, D. S., & Bartels, T. pTSara-NatB, an improved N-terminal acetylation system for recombinant protein expression in E. coli. PloS One13(7), e0198715. (2018). Rovere, M., Sanderson, J. B., Fonseca-Ornelas, L., Patel, D. S., & Bartels, T. Refolding of helical soluble α-synuclein through transient interaction with lipid interfaces. FEBS Letters592(9), 1464–1472. (2018)

  2. Rovere, M., Sanderson, J. B., Fonseca-Ornelas, L., Patel, D. S., & Bartels, T. Refolding of helical soluble α-synuclein through transient interaction with lipid interfaces. FEBS Letters592(9), 1464–1472. (2018)
  3. Schapansky, J., Khasnavis, S., DeAndrade, M. P., Nardozzi, J. D., Falkson, S. R., Boyd, J. D., Sanderson, J., Bartels, T., Melrose, H., LaVoie, M. Familial knockin mutation of LRRK2 causes lysosomal dysfunction and accumulation of endogenous insoluble α-synuclein in neurons. Neurobiol Dis111, 26–35. (2018)

  4. Dettmer, U., Ramalingam, N., von Saucken, V., Kim, T., Newman, A., Terry-Kantor, E., Nuber, S., Ericsson, M., Fanning, S., Bartels, T., Lindquist, S., Levy, O., Selkoe, D. Loss of native a-synuclein multimerization by strategically mutating its amphipathic helix causes abnormal vesicle interactions in neuronal cells. HMG26, 3466–3481 (2017).

  5. Mittal, S., Bjornevik, K., Im, D., Flierl, A., Dong, X., Locascio, J., About, K., Long, E., Jin, M., Bing, X., Xiang, Y., Rochet, J., England, A., Rizzu, P., Heutnink, H., Bartels, T., Selkoe, D., Calderone, B., Glicksman, M., Khurana, V., Schüle, B., Park, D., Riise, T., Scherzer, C. b2-Adrenoreceptor is a regulator of the a-synuclein gene driving risk of Parkinson’s disease. Science 357, 891–898 (2017).

  6. Bartels, T. Conformation-Specific Detection of α-Synuclein: The Search for a Biomarker in Parkinson Disease. JAMA Neurol., (2016).

  7. Dettmer, U., Selkoe, D. & Bartels, T. New insights into cellular α-synuclein homeostasis in health and disease. Curr. Opin. Neurobiol. 36, 15–22 (2015).

  8. Bartels, T. Conformation-Specific Detection of α-Synuclein: The Search for a Biomarker in Parkinson Disease. JAMA Neurol., (2016).

  9. Dettmer, U., Selkoe, D. & Bartels, T. New insights into cellular α-synuclein homeostasis in health and disease. Curr. Opin. Neurobiol. 36, 15–22 (2015).

  10. Dettmer, U., Newman, A. J., Saucken, von, V. E., Bartels, T. & Selkoe, D. KTKEGV repeat motifs are key mediators of normal α-synuclein tetramerization: Their mutation causes excess monomers and neurotoxicity. PNAS 112, 9596–9601 (2015).

  11. Luth, E. S., Bartels, T., Dettmer, U., Kim, N. C. & Selkoe, D. J. Purification of α-synuclein from human brain reveals an instability of endogenous multimers as the protein approaches purity. Biochemistry 54, 279–292 (2015).

  12. Dettmer, U. , Newman, A. J., Soldner, F. Luth, E., Kim, N. Saucken, von, V. E., Sanderson, J., Jaenisch, R., Bartels, T. & Selkoe, D. Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation. Nat Commun 6, 7314 (2015).

  13. Luth, E. S., Stavrovskaya, I. G., Bartels, T., Kristal, B. S. & Selkoe, D. J. Soluble, Prefibrillar α-Synuclein Oligomers Promote Complex I-dependent, Ca2+-induced Mitochondrial Dysfunction. The Journal of biological chemistry 289, 21490–21507 (2014).

  14. Hong, S., Ostaszewski, B., Yang, T. O’Malley, T., Jin, M., Yanagisawa, K., Li, S., Bartels, T. & Selkoe, D. Soluble Aβ oligomers are rapidly sequestered from brain ISF in vivo and bind GM1 ganglioside on cellular membranes. Neuron 82, 308–319 (2014).

  15. Bartels, T., Kim, N. C., Luth, E. S. & Selkoe, D. J. N-Alpha-Acetylation of α-Synuclein Increases Its Helical Folding Propensity, GM1 Binding Specificity and Resistance to Aggregation. PLoS ONE 9, e103727 (2014).

  16. Selkoe, D. Dettmer, U., Luth, E., Kim, N., Newman, A., Bartels, T. Defining the native state of α-synuclein. Neurodegener Dis 13, 114–117 (2014).

  17. Dettmer, U., Newman, A. J., Luth, E. S., Bartels, T. & Selkoe, D. In vivo cross-linking reveals principally oligomeric forms of α-synuclein and β-synuclein in neurons and non-neural cells. The Journal of biological chemistry 288, 6371–6385 (2013).

  18. Bartels, T., Choi, J. G. & Selkoe, D. J. α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature 477, 107–110 (2011).

  19. Kamp, F., Exner, N., Lutz, A., Wender, N., Degerman, J., Brunner, B.,Nuscher, B., Bartels, T., Giese, A., Beyer, K., Eimer, S., Winklhofer, K., Haass, C. Inhibition of mitochondrial fusion by α-synuclein is rescued by PINK1, Parkin and DJ-1. EMBO J. 29, 3571–3589 (2010).

  20. Bartels, T. et al. The N-terminus of the intrinsically disordered protein α-synuclein triggers membrane binding and helix folding. Biophysical journal 99, 2116–2124 (2010).

  21. Bartels, T., Lankalapalli, R. S., Bittman, R., Beyer, K. & Brown, M. F. Raftlike mixtures of sphingomyelin and cholesterol investigated by solid-state 2H NMR spectroscopy. Journal of the American Chemical Society 130, 14521–14532 (2008).