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AG Tikkanen

Rare Diseases Research Group

The main research interest of our group are the molecular mechanisms of rare diseases and development of personalized therapies for such diseases. The spectrum of diseases in our research focus include lysosomal storage disorders (aspartylglucosaminuria, neuronal ceroid lipofuscinoses), disorders of neurotransmitter metabolism (SSADH deficiency), and autoimmune diseases (Pemphigus). In addition, the molecular mechanisms of cancers, especially those dependent on MAP kinase signaling, are addressed in our group. 

 

Aspartylglucosaminuria (R. Tikkanen and A. Banning)

Aspartylglucosaminuria (AGU) is a rare genetic disorder caused by mutations in the gene encoding for the lysosomal enzyme aspartylglucosaminidase (AGA). AGU patients are born seemingly normal, but within the first years of life, they start lagging behind in their development and become increasingly handicapped and intellectually disabled by early adulthood. Currently, no approved therapies are available for AGU.  

Our group focuses on characterization of the molecular consequences of the AGU mutations, with the aim of developing individual therapies for AGU. Our approaches include pharmacological chaperones (PC) and nonsense read-through drugs, and we are also involved in developing gene therapy for AGU. So far, we have developed two PC therapies that are currently tested in patients (Banning et al. 2016). An investigator-initiated clinical trial with one of these substances is currently undergoing in Finland, together with Dr. Minna Laine, a child neurologist at Helsinki University Hospital (see: https://pediatricresearchcenter.helsinki.fi/137-a-novel-therapy-trial-for-agu-disease-at-huch.html). For patients exhibiting nonsense mutations combined with certain missense mutations, we have shown that substances that inhibit the nonsense-mediated decay of mRNA and induce a translational read-through of the nonsense codon are beneficial in AGU and result in increased enzyme activity in patient cells (Banning et al. 2018). One of these substances is also currently tested in an individual clinical trial.

Gene therapy approach for AGU is currently being developed in collaboration with UTSW researchers, especially Dr. Steven Gray (see: https://www.med.unc.edu/genetherapy/research-laboratories/gray-lab/) .

 

Neuronal Ceroid Lipofuscinoses (R. Tikkanen and A. Zakrzewicz)

Neuronal ceroid lipofuscinoses (NCL) are a group of lysosomal storage disorders that result in a severe developmental delay associated with vision loss and epileptic seizures that are difficult to control. Depending on the respective gene defect, these diseases show a different age of onset and disease progression and are classified into various forms (CLN1 - CLN14). Our group is interested in the classic late infantile (cLINCL, CLN2) and juvenile (JNCL, CLN3) forms. Therapies are available for only very few NCL forms.

We have previously shown that specific membrane lipids termed gangliosides exhibit altered amounts in JNCL (Somogyi et al. 2018). Especially the ganglioside GM3 accumulates in high amounts, whereas other gangliosides such as GM1 are reduced. Since balanced amounts of various gangliosides are vital for normal brain development, we are currently testing if modulation of ganglioside amounts in NCLs might have a therapeutic effect.

Also in NCL diseases, we are interested in developing therapies that are based on similar strategies as described above for AGU, namely read-through therapies and pharmacological chaperones. Since certain nonsense mutations are very common especially in cLINCL patients, the read-through approach may provide a means to treat a large number of patients with the same drug. 

 

SSADH Deficiency (R. Tikkanen)

Succinyl semialdehyde dehydrogenase (SSADH) is a mitochondrial enzyme involved in the catabolism of the neurotransmitter GABA. SSADH deficiency (SSADH-D) is a genetic disorder caused by mutations in the gene encoding the SSADH enzyme. In the absence of SSADH activity, GABA and its metabolite GHB accumulate in the tissues and cause mainly neuronal and muscular deficits. Our current research interests are the characterization of the molecular consequences of SSADH mutations and testing of various therapy options in cell culture models. As with AGU and NCLs, we are interested in identifying PC substances that would restore the missing SSADH activity, and probing for the read-through therapies. In addition, we are developing strategies suitable for enzyme replacement and gene therapy for SSADH-D.             

 

Function of Flotillin Proteins in Cell Adhesion: Molecular Mechanisms of Pemphigus Vulgaris (R. Tikkanen and A. Banning)

Our current work includes the characterization of the molecular function of the flotillin family of proteins. Flotillins were originally described as neuronal regeneration proteins that are upregulated in the regenerating axons of gold fish retinal ganglion cells after a lesion of the optic nerve and thus named “reggies” for regeneration. Later studies have shown that flotillins are ubiquitously expressed, highly conserved and associated with membrane rafts. Our previous work has focused on characterization of flotillin function in signal transduction and cell adhesion. We have shown that flotillins are involved in both cell-matrix and cell-cell adhesion (Banning et al. 2018, Völlner et al. 2016). We could show that flotillins are involved in the regulation of desmosomal adhesion in the epidermis, and they interact with the desmosomal cadherin proteins and plakoglobin (Völlner et al. 2016).

Our current research focuses on elucidating the molecular mechanism of how desmosomal adhesion is regulated by flotillins, and how flotillins modulate the desmosomal adhesion in the severe autoimmune skin disease Pemphigus Vulgaris (PV). In PV, autoantibodies against desmosomal adhesion proteins, mainly desmoglein-3, cause severe blistering of the epidermis and mucosa due to loss of desmosomal adhesion in epidermal keratinocytes. The mechanisms of adhesion loss are as yet not completely characterized, but signaling and vesicle trafficking are likely to play a role. Flotillins are known to be involved in both signaling and membrane trafficking, and we are currently studying how flotillins modulate these processes in the context of Pemphigus. We are members in the DFG-funded Research Focus FOR 2497 “Pemphigus - from Pathogenesis to Therapy (Pegasus)”. (www.pegasus-dfg.de). In addition to their role in the regulation of desmosomes in the epidermis, we are also interested in how flotillins affect desmosomal adhesion in the cardiac tissue (Kessler et al. 2018).      

Flotillins in Cancer and as Regulators of MAP Kinase Signaling

Our recent findings show that depletion of flotillin-1 results in a severe impairment of EGF receptor signaling. Not only the activation of the EGF receptor is inhibited, but also the downstream signaling towards the MAP kinase cascade (Amaddii et al. 2012). We could show that flotillin-1 directly interacts with several proteins of the MAP kinase pathway, including CRAF, MEK1 and ERK2 and thus most likely functions in regulating the signaling at the level of MAPK signalosomes. Flotillins are frequently overexpressed in various types of cancers, and our research aims at characterizing the link between flotillin function and cancer/metastasis formation.


Recent Publications (selection)

  1. Somogyi A, Petcherski A, Beckert B, Huebecker M, Priestman DA, Banning A, Cotman SL, Platt FM, Ruonala MO, Tikkanen R. (2018) Altered expression of ganglioside metabolizing enzymes results in GM3 ganglioside accumulation in cerebellar cells of a mouse model of juvenile neuronal ceroid lipofuscinosis. Int J Mol Sci, 19, 625; doi:10.3390/ijms19020625
  2. Banning A, Schiff M, Tikkanen R. (2018) Amlexanox Provides a Potential Therapy for Nonsense Mutations in the Lysosomal Storage Disorder Aspartylglucosaminuria. BBA - Molecular Basis of Disease, pii: S0925-4439(17)30463-5. doi: 10.1016/j.bbadis.2017.12.014
  3. Banning A, Babuke T, Kurrle N, Meister M, Ruonala MO, Tikkanen R. (2018) Flotillins regulate focal adhesions by interacting with α-actinin and by influencing the activation of Focal Adhesion Kinase. Cells, 7, 28; doi:10.3390/cells7040028
  4. Kessler EA, van Stuijvenberg L, van Bavel JJA, van Bennekom J, Zwartsen A, Rivaud MA, Vink A, Efimov IA, van Tintelen JP, Remme CA, Marc A. Vos MA, Banning A, de Boer TP, Tikkanen R, van Veen TAB. (2018) Flotillins in the intercalated disc are potential modulators of cardiac excitability. In press, J Mol Cell Cardiol 2018 Nov 16. pii: S0022-2828(18)30540-6. doi: 10.1016/j.yjmcc.2018.11.007.
  5. Meister M, Baenfer S, Gärtner U, Koskimies J, Amaddii M, Jacob R, Tikkanen R. (2017) Regulation of cargo transfer between ESCRT-0 and ESCRT-I complexes by flotillin-1 during endosomal sorting of ubiquitinated cargo. Oncogenesis 6, e344; doi:10.1038/oncsis.2017.47
  6. Banning A, König JF, Gray SJ, Tikkanen R. (2017) Functional Analysis of the Ser149/Thr149 Variants of Human Aspartylglucosaminidase and Optimization of the Coding Sequence for Protein Production . Int J Mol Sci, 18, 706; doi:10.3390/ijms18040706
  7. Banning A, Gülec C, Rouvinen J, Gray SJ, Tikkanen R. (2016) Identification of Small Molecule Compounds for Pharmacological Chaperone Therapy of Aspartylglucosaminuria. Sci. Rep. 6, 37583; doi: 10.1038/srep37583
  8. Völlner F, Ali J, Kurrle N, Exner Y, Eming R, Hertl M, Banning A, Tikkanen R. (2016) Loss of flotillin expression results in weakened desmosomal adhesion and Pemphigus vulgaris-like localisation of desmoglein-3 in human keratinocytes. Sci Rep, 6, 28820; DOI:10.1038/srep28820
  9. Kapahnke M, Banning A, Tikkanen R. (2016) Random splicing of several exons caused by a single base change in the target exon of CRISPR/Cas9 mediated gene knockout. Cells 5, 45; doi:10.3390/cells5040045
  10. Banning A, Regenbrecht CRA, Tikkanen R. (2014) Increased activity of mitogen activated protein kinase pathway in flotillin-2 knockout mouse. Cell Signal, 26(2), 198-207. doi: 10.1016/j.cellsig.2013.11.001
  11. Meister M, Zuk A, Tikkanen R. (2014) Role of dynamin and clathrin in cellular trafficking of flotillins. FEBS J, 281, 2956–2976. doi: 10.1111/febs.12834
  12. John BA, Meister M, Banning A, Tikkanen R. (2014) Flotillins bind to the Dileucine Sorting Motif of BACE1 and influence its endosomal Sorting. FEBS J, 281, 2074–2087. doi: 10.1111/febs.12763.
  13. 13.   Mooz J, Oberoi-Khanuja TK, Harms GS, Wang W, Tikkanen R, Jaiswal BS, Seshagiri S, Rajalingam K. (2014) Dimerization of ARAF promotes MAPK activation and cell migration. Science Signaling, 7(337):ra73. doi: 10.1126/scisignal.2005484
  14. Fork C, Hitzel J, Nichols BJ, Tikkanen R, Brandes RP. (2014) Flotillin-1 facilitates Toll-like receptor 3 signaling in human endothelial cells. Basic Res Cardiol, 109:439. doi: 10.1007/s00395-014-0439-4
  15. Kurrle N, Völlner F, Eming R, Hertl M, Banning A, Tikkanen R. (2013) Flotillins directly interact with γ-catenin and regulate cell-cell adhesion. PLoS ONE, 8(12):e84393 doi: 10.1371/journal.pone.0084393
  16. Amaddii M*, Meister M*, Banning A, Tomasovic A, Mooz J, Rajalingam K, Tikkanen R. (2012) Flotillin-1/reggie-2 plays a dual role in the activation of receptor tyrosine kinase/MAP kinase signaling. J Biol Chem, 287(10):7265-78
  17. Chapuy B, Tikkanen R, Mühlhausen C, Wenzel D, von Figura K, Höning S. (2008) The AP-1 and AP-3 adaptor complexes mediate sorting of melanosomal and lysosomal membrane proteins into distinct post-Golgi trafficking pathways. Traffic, 9: 1157-1172
  18. Icking A, Amaddii M, Ruonala M, Höning S, Tikkanen R. (2007) Polarized transport of Alzheimer Amyloid Precursor Protein is mediated by adaptor complex AP-1B. Traffic, 8: 285-296
  19. Neumann-Giesen C, Fernow I, Amaddii M, Tikkanen R. (2007) Role of EGF-induced Tyrosine Phosphorylation of Reggie-1/Flotillin-2 in Cell Spreading and Signaling to Actin Cytoskeleton. J Cell Sci, 120: 395-406
  20. Babuke T, Tikkanen R. (2007) Dissecting the molecular function of reggie/flotillin proteins. Eur J Cell Biol, 86: 525–532 (review)
  21. Schilling K, Opitz N, Wiesenthal A, Oess S, Tikkanen R, Müller-Esterl W, Icking A. (2006) Translocation of endothelial NO synthase involves a ternary complex with caveolin-1 and NOSTRIN. Mol Biol Cell, 17: 3870-80
  22. Jakob V, Schreiner A, Tikkanen R, Starzinski-Powitz A. (2006) Targeting of transmembrane protein shrew-1 to adherens junctions is controlled by cytoplasmic sorting motifs. Mol Biol Cell, 17: 3397-3408
  23. Hoeller D, Crosetto N, Blagoev B, Raiborg C, Tikkanen R, Wagner S, Kowanetz K, Breitling R, Mann M, Stenmark H, Dikic I. (2006) Regulation of ubiquitin-binding proteins by monoubiquitination. Nature Cell Biol, 8: 163-169
 

 

For a complete list of publications of Ritva Tikkanen, see Pubmed