Protein glycosylation in ageing-related diseases through study of Down syndrome as accelerated ageing condition
This project is supported by the “Research Cooperability“ Program of the Croatian Science Foundation funded by the European Union from the European Social Fund under the Operational Programme Efficient Human Resources 2014- 2020.
Project acronym: GlycoDown
Name of the project: Protein glycosylation in ageing-related diseases through study of Down syndrome as accelerated ageing condition (Project ID: PZS-2019-02-4277)
Project start date: 1 October 2019
Project end date: 31 May 2023
Project Leader: Prof. Gordan Lauc
Project Co-leader: Prof. Dean Nižetić, Queen Mary University of London
The total value of the project: 2.200.000,00 HRK
For more information, please contact: prof. Gordan Lauc, project leader, email@example.com
A short description of the project:
Croatia (and the whole of Europe) are suffering from the most unfavourable demographic trends. They include high population-ageing rates, and an increasing incidence of age-related cognitive impairment, Alzheimer’s dementia (AD) and other ageing-related diseases. Recently, immunoglobulin G (IgG) glycome pattern has been reported to be an accurate biomarker of chronological and biological ageing, as well as systemic inflammation.
The most useful models to study ageing mechanisms are conditions with accelerated ageing due to genetic causes. Down’s Syndrome (DS) (trisomy 21 (T21)) causes extremely accelerated cellular and organism ageing. However, despite this, and despite genetic reasons that cause early Alzheimer’s disease neuropathology, significant cohorts of people with DS are protected from ageing-related diseases, such as clinical dementia (30% individuals), cancer, atherosclerosis and diabetes, despite the strong risk factors. Prof. Nižetić is an internationally leading researcher in DS, in relation to ageing, stem cell biology and cancer. His team recently developed and published a new isogenic induced pluripotent stem cell (iPSC) model of DS, which is, to our knowledge the first iPSC model (of any disease) to show accelerated neuronal ageing. In this model, T21 causes a significantly increased number of γH2AX foci (a marker of cellular ageing) in iPSC and neurons derived from them. It also shows T21-caused amyloid-β- peptide accumulation (an AD hallmark), and other accelerated neuronal ageing-phenotypes, such as mitochondrial abnormalities.
Protein glycosylation has never been systematically studied in the context of DS. In our preliminary data from plasma samples of 10 DS individuals, compared to age-matched euploids, we detected extreme values in several glycan forms of IgG, indicating that markers of extremely accelerated ageing can be detected by studying glycome perturbations in DS.
The project goals and expected results:
The major goals of this project are: (i) to determine glycosylation of immunoglobulin G (IgG) in Down Syndrome (DS) by analysing 300 individuals with DS from 3 European population. In addition, they will be analysed based on co-morbidities, in particular early or late/absent onset of AD, with the goal to establish novel glycan biomarkers of AD and/or biomarkers for other diseases present in individuals with DS such as autoimmune diseases; (ii) to examine the effect of specific chromosome 21 gene products, B3GALT5, RUNX1 and DYRK1A, on the glycosylation profiles; (iii) to establish the effects of T21 on glycan profiles by comparing isogenic iPSCs that differ only on the presence of T21; (iv) to search for novel glycan bio-markers predictive of early AD by comparing glycan profiles in iPSCs (and derived cerebral organoids as well as pure populations of neurons, astrocytes and microglia) from DS subjects with early dementia (in their 30s) with DS subjects with no dementia at age >60.
We expect that IgG glycan profiles in Down Syndrome individuals will show extreme profiles that reflect accelerated aging. In addition, glycosylation profile of individuals with DS may exhibit some unique characteristics compared to healthy controls, not seen with ageing in the general population. It can be expected that IgG glycan markers that correlate with systemic inflammation might correlate with specific co-morbidities in DS adults (particularly with the presence/absence of autoimmune diseases and/or dementia, and/or age of onset). Next, we expect that T21 will cause significant glycome-profile alterations in iPSCs and specific cell types derived from iPSCs (neurons, astrocytes and microglia). Such changes could then be exploited as early pre-morbid biomarkers with predictive values for specific ageing-related diseases such as Alzheimer’s dementia. Those newly discovered biomarkers would then serve not only to people with DS, but to the general ageing population.