Post-translation Modifications of the Synaptic Scaffold Controlling Age-Induced Memory Impairment (SyMetAge)

Age-dependent memory impairment (AMI) emerged as a widespread health threat during the last century and has since been affecting the quality of life for many senior citizens. AMI is characterised by symptoms of cognitive decline. Typically, it starts in mid-life and deepens with advancing age, suggesting that age itself is the greatest risk factor. But why do the elderly develop memory deficits? Investigations of brain regions with crucial roles in cognitive processing point towards age-related changes of synaptic structure and plasticity. However, causal relationships between these synaptic changes and AMI have yet to be established. The central hypothesis of the project »Post-translation Modifications of the Synaptic Scaffold Controlling Age-Induced Memory Impairment (SyMetAge)« is that an age-associated change in post-translational modifications (PTMs) provokes alterations in structural and functional plasticity of synapses. PTMs include, for example, phosphorylation, acetylation, methylation, ubiquitylation and neddylation. These modifications significantly affect the structure and dynamics of proteins and play a key role in numerous biological processes. »SyMetAge« aims to establish causal relations between lifetime-associated PTMs and memory impairment as well as deliver a conceptual frame for a mechanistic understanding of the phenomenon.

Molecular fingerprints of synapse ageing

The goal of this project is to establish a model of AMI that bridges the molecular status of identified memory-forming synapses with the behavioural display of memory. The project will lay the foundations for establishing AMI’s molecular fingerprints and identifying essential entry points for interventions in the cognitive decline.

»SyMetAge«’s primary objectives are:

1. Identifying dynamic phosphorylation events causally related to AMI.

2. Clarifying the role of specific phosphorylation events in modulating ageing-related functional and structural changes in presynaptic active zones.

3. Investigating how the mass relations in protein phosphorylation contribute to AMI by upshifting the size and release function of presynaptic active zones (RAMP-UP).

4. Identifying the molecular fingerprints of synapse ageing and age-induced memory impairment.

5. Determining the heterogeneity of acetylation, methylation, ubiquitylation, and neddylation at crucial lysine residues of memory relevant synaptic proteins.

To accomplish these, researchers at ISAS, are currently analysing peptide samples using proteomics approaches based on Liquid chromatography–mass spectrometry.