Protein glycosylation in aging-related diseases through the study of Down syndrome as an accelerated aging 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 aging-related diseases through the study of Down syndrome as accelerated aging 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, firstname.lastname@example.org
A short description of the project:
Croatia (and the whole of Europe) are suffering from the most unfavorable demographic trends. They include high population-aging rates, and an increasing incidence of age-related cognitive impairment, Alzheimer’s dementia (AD), and other aging-related diseases. Recently, the immunoglobulin G (IgG) glycome pattern has been reported to be an accurate biomarker of chronological and biological aging, as well as systemic inflammation.
The most useful models to study aging mechanisms are conditions with accelerated aging due to genetic causes. Down’s Syndrome (DS) (trisomy 21 (T21)) causes extremely accelerated cellular and organism aging. However, despite this, and despite genetic reasons that cause early Alzheimer’s disease neuropathology, significant cohorts of people with DS are protected from aging-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 aging, 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 aging. In this model, T21 causes a significantly increased number of γH2AX foci (a marker of cellular aging) in iPSC and neurons derived from them. It also shows T21-caused amyloid-β- peptide accumulation (an AD hallmark), and other accelerated neuronal aging-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 aging 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 the glycosylation of immunoglobulin G (IgG) in Down Syndrome (DS) by analyzing 300 individuals with DS from 3 European populations. In addition, they will be analyzed 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, the glycosylation profile of individuals with DS may exhibit some unique characteristics compared to healthy controls, not seen with aging 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 aging-related diseases such as Alzheimer’s dementia. Those newly discovered biomarkers would then serve not only to people with DS but to the general aging population.