PhD Project - The impact of autism on synapse proteostasis

Vacancy Reference Number
2022-SIDB-GRANT
Closing Date
16 Jan 2022
Address
University of Edinburgh

Background:

Synapse proteins are constantly being synthesised and degraded and this allows for remodelling during development and for maintenance and repair in adulthood. Protein turnover is required for synaptic plasticity and memory, and many forms of autism are caused by mutations that interfere with protein turnover(1). Because of the technical challenges of measuring protein turnover in individual synapses in the intact brain, it is not known whether there are differences in the rate of protein turnover between synapses. This is particularly important because it is now clear that there is a striking and previously unappreciated diversity of excitatory synapses in the brain and that diseases can target different synapses(2, 3). That synapse protein turnover rates may differ across the dendritic tree of neurons is suggested by the observation that dendrites contain protein synthesis and degradation machinery(4). We have developed tools that permit the study of synapse protein turnover at single-synapse resolution across the whole mouse brain at any age. We find that excitatory synapses with different protein lifetimes are differentially distributed in dendrites, neuron types and brain regions. Crucially, we have preliminary evidence in two autism mouse models that synapse subtypes with rapid protein turnover rates are specifically targeted in autism.

Rationale & hypothesis:

We hypothesise that a convergent pathological mechanism of autism is the damage to specific subsets of excitatory synapses with rapid protein turnover, and that this damage prevents normal synaptome remodelling in development. Identifying and characterising these autism-vulnerable synapse subtypes could provide entirely novel avenues for therapeutic intervention. 

Aims:

The student will: 1. Characterise synapse protein turnover at single-synapse resolution in mouse models of autism, including the Ube3A mutant as a model of Angelman syndrome. Pre- and postsynaptic proteins from excitatory and inhibitory synapses will be evaluated. 2. Uncover the spatiotemporal architecture of autism impacts during brain development, tracing the vulnerable and resistant synapse types. 3. Test the capacity of interventions with therapeutic potential that correct synapse protein turnover pathology. 4. Disseminate the autism disease signatures via the Protein Lifetime Synaptome Atlas to maximise the potential health impact of the project outputs.

Training outcomes:

The student will gain experience in multidisciplinary aspects of contemporary neuroscience including the use of genetically modified mice, molecular imaging using confocal and super-resolution microscopy, methods for cell-type-specific regulation, proteomics, state-of-the-art computational image analysis, large dataset management, modelling, and atlas building. The student will actively participate in collaborations with laboratories performing live imaging, electrophysiological, anatomical and behavioural studies.