Grimm Lab

Head of lab

Prof. Dr. rer. nat. Dr. phil. Christian Michael Grimm

We focus on the physiological roles and activation mechanisms of endolysosomal ion channels

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Lysosomal dysfunction can result in lysosomal storage disorders (LSDs) such as mucolipidoses but it is also implicated in the development of more common neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, metabolic diseases, retinal diseases and pigmentation disorders, trace metal deficiencies such as iron deficiency, and also cancer and immune diseases. Highly critical for the proper function of lysosomes, endosomes, and lysosome-related organelles (LROs) is the tight regulation of various fusion and fission processes and the regulation of proton and other cation concentrations within the endolysosomal system (ES). TRPML cation channels (TRPML1, 2 and 3) and Two-pore channels (TPC1, TPC2) have recently emerged as important regulators of such processes within the ES and appear to be essential for a proper communication between the various endolysosomal vesicles. We use endolysosomal patch-clamp techniques, molecular and cell biology techniques as well as knockout mouse models to study the physiological roles and activation mechanisms of these ion channels in more detail with the ultimate aim to explore the potential of these ion channels as drug targets for a range of different diseases.

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iPSC culture

Induced pluripotent stem cells (iPSCs) are a type of stem cell that can be generated by reprogramming adult cells, such as skin cells, back into a pluripotent state.

iPSCs have the remarkable ability to differentiate into various cell types found in the body, including neurons, heart cells, and liver cells. Studying the effects of LSD mutations can be achieved by differentiating neurons into cortical and dopaminergic types. These neurons are then subjected to treatment with various compounds in order to identify potential future therapies for associated diseases

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Opera Phenix High-Content Imager

The Opera Phenix is an advanced imaging system that utilizes a confocal spinning disc microscope for high-content imaging. It enables rapid data acquisition across multiple wells in high magnification formats, making it highly efficient. With the help of automated analysis algorithms, it enables unbiased acquisition and analysis of data. Moreover, it offers CO2 and temperature regulation, facilitating live imaging experiments.

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Endolysosomal Patch-Clamp

Endolysosomal patch-clamp is a technique used for electrophysiological characterization of ion channels present in endolysosomal membranes. It involves creating a patch-clamp configuration on the membrane of enlarged endolysosomal vesicles. By applying voltage and recording the resulting electrical activity, detailed insights into the function and regulation of endolysosomal ion channels can be gained, which play important roles in cellular processes and disease mechanisms.

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Confocal Imaging

Confocal imaging is a technique used to capture high-resolution images of samples, such as cells or tissues, with improved clarity and contrast. It works by using a pinhole to eliminate out-of-focus light, resulting in sharper images with better optical sectioning. By scanning the sample point by point, confocal imaging enables three-dimensional reconstruction and visualization of the specimen.

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Ca2+ Imaging

In the research of TRPML and TPC channels, Ca2+-imaging is used to investigate the activity of calcium ions in cells. By using fluorescent dyes that bind to Ca2+, real-time changes in Ca2+ levels can be visualized. Analyzing Ca2+ fluctuations provides insights into the function and regulation of these channels, which can contribute to the development of potential treatments for associated diseases.

Publications

Martucci LL, Launay JM, Kawakami N, Sicard C, Desvignes N, Dakouane-Giudicelli M, Spix B, Têtu M, Gilmaire F-O, Paulcan S, Callebert J, Vaillend C, Bracher F, Grimm C, Fossier P, de la Porte S, Sakamoto S, Morris J, Galione A, Granon S, Cancela J-M: Endo-lysosomal two-pore channels regulate social behaviour by controlling oxytocin and vasopressin secretion. PNAS 2023 120(7):e2213682120. doi: 10.1073/pnas.2213682120.

Laqtom NN, Dong W, Medoh UN, Cangelosi AL, Dharamdasani V, Chan SH, Kunchok T, Lewis CA, Heinze I, Tang R, Grimm C, Do AND, Porter FD, Ori A, Sabatini DM, Abu-Remaileh M: CLN3 is required for the efflux of glycerophosphodiesters from lysosomes. Nature 2022 Sep 21. doi: 10.1038/s41586-022-05221-y.

Scotto Rosato A*, Krogsaeter E*, Jaślan D, Abrahamian C, Montefusco S, Soldati C, Spix B, Böck J, Pizzo, MT, Grieco, G., Wyatt A, Wünkhaus D, Passon M, Stieglitz M, Keller M, Hermey G, Markmann S, Gruber-Schoffnegger D, Cotman S, Johannes L, Crusius D, Boehm U, Wahl-Schott C, Biel M, Bracher F, De Leonibus, E, Polishchuk E, Medina DL, Paquet D, Grimm C#: TPC2 rescues lysosomal storage in mucolipidosis type IV, Niemann-Pick type C1 and Batten disease. EMBO Mol Med 2022.Sep 7;14(9):e15377. doi: 10.15252/emmm.202115377.

Yuan Y, Jaślan D, Rahman T, Bolsover SR, Arige V, Wagner LE, Abrahamian C, Keller M, Hartmann J, Scotto Rosato A, Weiden E-M, Bracher F, Yule DI, Grimm C#, Patel, S: Segregated cation flux by TPC2 biases Ca2+ signaling through lysosomes. Nature Commun 2022 Jan 14;13(1):318. doi: 10.1038/s41467-021-27860-x.

Spix B, Butz ES, Chen C-C, Scotto Rosato A, Tang R, Jeridi A, Kudrina V, Plesch E, Wartenberg P, Arlt E, Briukhovetska D, Ansari M, Günes Günsel G, Conlon TM, Wyatt A, Wetzel S, Teupser D, Holdt LM, Ectors F, Boekhoff I, Boehm U, García-Añoveros J, Saftig P, Giera M, Kobold S, Schiller HB, Zierler S, Gudermann T, Wahl-Schott C, Bracher F, Yildirim AÖ, Biel M, Grimm C#: Lung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice. Nature Commun 2022 Jan 13(1):318. doi: 10.1038/s41467-021-27860-x.

Soldati C, Lopez-Fabuel I, Wanderlingh LG, Garcia-Macia M, Monfregola J, Esposito A, Napolitano G, Guevara-Ferrer M, Scotto Rosato A, Krogsaeter EK, Paquet D, Grimm C, Montefusco S, Braulke T, Storch S, Mole SE, De Matteis MA, Ballabio A, Sampaio JL, McKay T, Johannes L, Bolaños JP, Medina DL. Repurposing of tamoxifen ameliorates CLN3 and CLN7 disease phenotype. EMBO Mol Med 2021 Aug 19:e13742. doi: 10.15252/emmm.202013742. Online ahead of print.

Chen C-C, Krogsaeter E, Butz E, Li Y, Puertollano R, Wahl-Schott C, Biel M, Grimm C#: TRPML2 is an osmo-/mechano-sensitive cation channel in endolysosomal organelles. Science Adv, 6(46):eabb5064, 2020.

Arlt E, Fraticelli M, Tsvilovskyy V, Nadolni W, Breit A, O'Neill TJ, Resenberger S, Wennemuth G, Wahl-Schott C, Biel M, Grimm C, Freichel M, Gudermann T, Klugbauer N, Boekhoff I, Zierler S. TPC1 deficiency or blockade augments systemic anaphylaxis and mast cell activity. PNAS 2020 Jul 13:201920122. doi: 10.1073/pnas.1920122117. Online ahead of print. PMID: 32661165.

Scotto Rosato, A., Montefusco, S., Soldati, C., Di Paola, S., Capuozzo, A., Monfregola, J. Polishchuk, E., Amabile, A., Grimm, C., Lombardo, A., De Matteis, M.A., Ballabio, A., Medina, D.L. TRPML1 links lysosomal calcium to autophagosome biogenesis through the activation of the CaMKKβ/VPS34 pathway. Nature Commun 10:5630, 2019.

Goodridge, J., Jacobs, B., Saetersmoen, M., Clement, D., Clancy, T., Skarpen, E., Brech, A., Landskron, J., Grimm, C., Pfefferle, A., Meza-Zepeda, L., Lorenz, S., Thune Wiiger, M., Louch, W.E., Heggernes Ask, F., Liu. L.L., Yi Sheng Oei, V., Kjällquist, U., Linnarsson, S., Patel, S., Taskén, K., Stenmark, H., Malmberg, K.-J. TRPML1-mediated modulation of dense-core granules determines functional potential in NK cells. Nature Commun 2019 Jan 31;10(1):514. doi: 10.1038/s41467-019-08384-x.

Villella, V.R., Venerando, A., Cozza, G., Esposito, S., Ferrari, E., Monzani, R., Spinella, M.C., Oikonomou, V., Renga, G., Tosco, A., Rossin, F., Guido, S., Bear, C.E., Silano, M., Garaci, E., Chao, Y.-K., Grimm, C., Luciani, A., Romani, L., Piacentini, M., Raia, V., Kroemer, G. & Maiuri, L. A pathogenic role for cystic fibrosis transmembrane conductance regulator in celiac disease. EMBO J 2019 Jan 15;38(2). pii: e100101. doi: 10.15252/embj.2018100101. Epub 2018 Nov 29.

Chao Y-K, Schludi V, Chen C-C, Butz E, Nguyen, P., Müller, M., Krüger J, Kammerbauer C, Vollmar, A., Berking C, Biel M, Wahl-Schott C, Grimm C#: TPC2 polymorphisms associated with a human hair pigmentation phenotype result in gain of channel function by independent mechanisms. PNAS 114:E8595-E8602, 2017.

Chen C-C, Chunlei C, Fenske S, Butz E, Chao Y-K, Biel M, Ren D, Wahl-Schott C, Grimm C#: Patch clamp technique to characterize ion channels in individual intact endolysosomes. Nature Protoc 12:1639-1658, 2017.

Ruas M, Davis LC, Chen C-C, Morgan AJ, Chuang K-T, Walseth TF, Grimm C, Garnham C, Powell T, Biel M, Wahl-Schott C, Parrington J, Galione A: Expression of Ca²⁺-permeable two-pore channels rescues NAADP signalling in TPC-deficient cells. EMBO J 34:1743-1758, 2015.

Sakurai Y, Kolokoltsov AA, Chen C-C, Tidwell MW, Bauta WE, Klugbauer N, Grimm C, Wahl-Schott C, Biel M, Davey RA: Two pore channels control Ebolavirus host cell entry and are drug targets for disease treatment, Science 347:995-998, 2015.

Chen C-C, Keller M, Hess M, Schiffmann R, Urban N, Wolfgardt A, Schaefer M, Bracher F, Biel M, Wahl-Schott C, Grimm C#: A small molecule restores function to TRPML1 mutant isoforms responsible for mucolipidosis type IV. Nature Commun 5:4681, 2014.

Grimm C, Holdt LM, Chen C-C, Hassan S, Müller C, Jörs S, Cuny H, Kissing S, Schröder B, Butz E, Northoff B, Castonguay J, Luber CA, Moser M, Spahn S, Lüllmann-Rauch R, Fendel C, Klugbauer N, Griesbeck O, Haas A, Mann M, Bracher F, Teupser D, Saftig P, Biel M, Wahl-Schott C: High susceptibility to fatty liver disease in two-pore channel 2-deficient mice. Nature Commun 5:4699, 2014.

Aneiros E, Cao L, Papakosta M, Stevens EB, Phillips SC, Grimm C#: Biophysical and molecular basis of TRPV1 proton gating. EMBO J 30:994-1002, 2011.

Grimm C, Cuajungco MP, van Aken AFJ, Schnee M, Jörs S, Kros CJ, Ricci AJ, Heller S: A helix-breaking mutation in TRPML3 leads to constitutive activity underlying deafness in the varitint-waddler mouse. PNAS 104:19583-19588, 2007.

* authors contributed equally; # corresponding or shared corresponding author