Novel therapeutic approaches for neurodegenerative diseases and cancer by targeting proteoglycans.
Principal investigator; Mani, Katrin, Associate Professor, MD/PhD
Co-workers, not Lund University: Professor Brown David , Professor Cappai Roberto, Professor Gräslund Astrid , Professor Multhaup Gerd
The worldwide increasing age of populations brings the age related diseases such as neurodegenerative diseases and cancer into focus of interest. Protein folding is linked to the both family of diseases. We have discovered involvement of proteoglycans in formation and clearance of misfolded aggregation prone proteins and their dual role on cancer and neuronal cells survival. We have shown that recycling glypican-1 is involved in accumulation of scrapie in Mad-Cow disease (Cheng et al., J Neurochemistry 2006; Löfgren et al., 2008), and in clearance of amyloid beta in Alzheimer’s disease (Cheng et al., J. Biol. Chem. 2011), and oxidized aggregation-prone proteins in Niemann-Pick C1 disease (Mani et al., Glycobiology 2006; Mani et al., J Biol Chem.2007). We propose that glypican-1 is involved in protein quality control and function as chaperone by releasing supercharged glycosaminoglycan chains that form conjugates with aggregation-prone proteins targeting them to compartments involved in autosomal/lysosomal degradation (Mani et al, J Biol Chem. 2007; Fransson and Mani, Trends in Molecular Medicine 2007). Recently, we showed that HS oligo- and disaccharides derived from glypican-1 modulate and suppress oligomerization of amyloid beta 42 peptides. Further, we showed that vitamin C treatment dissolves toxic amyloid beta aggregates in hippocampus of Alzheimer’s mice by inducing release of HS oligosaccharides from glypican-1. We also found that dehydroascorbic acid, the oxidized form of vitamin C, is as effective. Our results show a previously unknown mechanism for how vitamin C affects amyloid formation and suggest important implications for therapy (Cheng et al., J Biol Chem. 2011).
During the past decade we have also been focusing on making artificial glycosaminoglycan priming compounds by synthesizing hydrophobic aromatic xylose-linked substances that can easily penetrate cell membranes as well as the blood-brain barrier and initiate glycosaminoglycan synthesis. Recently, using radiolabeled xylosides and co-cultures of normal stroma cells and breast cancer cells from patients with infiltrative ductal cancer we showed one such compound that preferentially inhibits growth of breast cancer cells by lowering acetylation of histone H3 indicating epigenetic effects (Nilsson et al., Cancer Research, 2010). We focus on an epigenetic approach, where small molecules that selectively influence the biosynthesis of glucosaminoglycan chains, make the transcription of DNA impossible and consequently force the cells into apoptosis. This approach has been tested in vitro and in vivo with very good results, i.e. 97% reduction of tumor load. The use of monosaccharides for anti-tumor treatment is a new and innovative approach.
By determining the physiological/pathophysiological role of proteoglycans in the clearance of misfolded proteins we aim to find new tools and therapeutic targets that affect the onset, progression, or regression of neurodegeneration and cancer growth. The knowledge will reveal novel mechanisms for regulation of protein stability and result in the development of novel preventive and therapeutic strategies for cancer and neurodegenerative diseases.
Link to project homepage: http://www.med.lu.se/expmed/forskning/glykobiologi
5 recent original publications
G. Svensson, W. Awad , K. Mani, D.T. Logan.
Crystal structure of N-glycosylated human glypican-1 core protein: Structure of two loops evolutionarily conserved in vertebrate glypican-1.
Journal of Biological Chemistry. 2012; 287: 14040-14051
F. Cheng, G. R. Cappai, G.D. Ciccotosto, G. Svensson, G. Multhaup, L.-Å. Fransson and K. Mani
Suppression of amyloid beta A11-immunoreactivity by vitamin C: possible role of heparan sulfate oligosaccharides derived from glypican-1 by ascorbate-induced, NO-catalyzed degradation.
Journal of Biological Chemistry. 2011; 286: 27559-27572
U. Nilsson, R. Johnsson, L.-Å. Fransson, U. Ellervik, and K. Mani
Attenuation of tumor growth by formation of antiproliferative glycosaminoglycans correlates with low acetylation of histone H3.
Cancer research. 2010; 70: 3771 - 3779
K. Löfgren, F. Cheng, L.-Å. Fransson, K. Bedecs, and K. Mani
Involvement of glypican-1 autoprocessing in scrapie infection.
European Journal of Neuroscience. 2008; 28: 964?972
L.-Å. Fransson, and K. Mani
Novel aspects of vitamin C: how important is glypican-1 recycling?
Trends in Molecular Medicine. 2007; 13: 143-149
Further publications here (new window)
|Total financing:||3.0 MSEK||Gov grant for clinical research ("ALF"):||0.0 MSEK|
|Total external financing:||2.0 MSEK||Natl and intl prioritized grants:||1.0 MSEK|