The Shahmoradian laboratory studies protein-lipid aggregation relevant to neurodegenerative disease, particularly in situ (within cells and tissues). 

We seek to understand the molecular architecture of such aggregates, their precursors and sub-cellular context, which would be critical in helping design more effective imaging tracers and therapeutic agents.

Multiple neurodegenerative diseases, including Alzheimer’s (AD) and Parkinson’s (PD),are associated with specific misfolded and aggregated proteins. 

Protein aggregation occurs when proteins adopt abnormal conformations or misfold, resulting in their association into larger, often insoluble structures.

Despite protein aggregation being heavily studied and visualized using recombinant proteins in vitro, little is known about near-native structure and specific disease-relevant conformation(s) in cells and tissues. 

This is partly because cellular space is very crowded, and teasing apart molecular-level details in such a crammed environment is a historical technical challenge. 

We develop and apply new interfaces and technologies for use in conjunction with cryo-focused ion beam milling (cryo-FIB) and cryo-electron tomography (cryo-ET) to reveal cellular architecture and molecular details of aggregates and their formation over time.

For example, we have created a compartmentalized neuronal co-culture platform allowing reconstruction of neuronal networks with high variable spatial control. 

Our platform is uniquely compatible for a specialized type of cryo-fixation that preserves all cellular components in a “vitreous”state without requiring chemical fixatives. 

All water in and around the sample is preserved in a transparent “glassy” state, avoiding the formation of cell-disruptive ice crystals.

This will enable us to capture and visualize the near-native state of molecular assemblies within cells and tissues. 

We use both cell culture and diseased tissues, together with biochemical and biophysical tools, to better understand the process of aggregate formation and to determine disease-relevant conformations.