January 19, 2018


Structural Pathogenesis

Investigating prion spread through the CNS

How do prion aggregates spread from cell-to-cell through the brain, and how does the prion quaternary structure impact the capacity to spread?

Prions are aggregated proteins that template the misfolding of the cognate cellular monomer, a process shared by other amyloidogenic proteins. Unlike the monomer, the aggregate is highly stable and poses challenges for cells to degrade. To clear prions, cells may degrade prions intracellularly through autophagy or release prions in exosomes or through unconventional secretion, contributing to further prion spread through the central nervous system.

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Defining how aggregates trigger neuronal toxicity

What are the molecular mechanisms that underlie neuronal degeneration? Do mechanisms of prion toxicity differ depending on the prion conformation? Which cells contribute to the synapse loss and neuronal death?

In addition to prions, amyloid-β and α-synuclein aggregates also bind to the cellular prion protein, triggering signaling cascades that accelerate neuronal degeneration. We have developed a new transgenic mouse model using CRISPR-Cas that shows hippocampal neuronal pathology similar to that in prion disease. Ultrastructurally, there are dystrophic neurites, indicating a failure of protein clearance mechanisms in neurons, as seen in the brains of patients with prion or Alzheimer’s disease.

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Investigating prion aggregation

What are the structural determinants of the prion protein that impact conversion? How can prion conversion be blocked?

The molecular mechanisms that underlie prion aggregation and transmission between species are poorly understood. Therefore another research focus is to identify the key residues and segments of the prion protein that control conversion and govern species barriers.

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