Prion Diseases Breakthroughs

Prion diseases are rare neurodegenerative diseases affecting one in every million people worldwide.  Some of the more common diseases are known as Creutzfeldt -Jakob disease in humans, or “Scrapie” in sheep and goats, Bovine Spongiform Encephalopathy (BSE) in cattle, and Chronic Wasting Disease in elk and mule deer.

Tanz Centre scientists have made some important discoveries in the field of prion diseases, including:

A) Tanz researchers co-discovered the “Doppel” (PRND) protein (2001 and 2004).

Doppel was the first family members of the PrP family to be discovered. We demonstrated that its biology is linked and antagonistic to PrP.

The discovery helped to shed light on the causes of a mysterious ataxic phenotype observed in a subset of PrP knockout mice. Since this seminal discovery, more than 150 papers have been published on Doppel and its relationship to PrP.

B) Demonstrating that the SPRN gene encodes a CNS expressed protein “Shadoo” with biochemical resemblance to PrP (2007).

Tanz scientists demonstrated that Shadoo confers protective activity in functional assays in cerebellar neurons. Most remarkably, steady state levels of the shadoo protein are markedly reduced in prion infected animals. A simple hypothesis emerged from this line of work which posits that clinical target areas in prion disease reflect loss of shadoo’s protective action.

C) Identification of the evolutionary origins and the mechanism of evolution of the prion protein (2009).

Tanz scientists discovered the evolutionary origins of the prion gene, best known for causing invariably fatal diseases in humans and livestock. Our subsequent work revealed that the prion founder gene emerged from a genomic insertion of a spliced and C-terminally truncated transcript of a ZIP metal ion transporter. These discoveries explained characteristics of the prion protein (PrP) as remnants of an ancient function in the sensing and transport of metal ions.

D) First PrP knockout cell models using CRISRP-Cas9 technology (2014).

Tanz scientists successfully generate a first PrP knockout cell model using a novel genetic engineering technology, known as CRISPR-Cas9. In total we reported the generation of three cell models, in which the ability of the cell to produce PrP was eliminated. These models have are now employed by several groups around in efforts to study the molecular biology of the PrP in health and disease.

E) Over the years, Tanz scientists have shaped our current understanding of the molecular environment of the prion protein (PrP).

In 2001, we identified the neural cell adhesion molecule (NCAM) as the most prominent next neighbor to PrP in neurons. In 2004, we identified more than two dozen proteins that reside in immediate proximity to PrP in the intact brain. In 2009 we reported the first study that investigated the molecular environment of PrP in a relevant cell model by comparative and quantitative mass spectrometry. Striking about these data was that the majority of proteins we observed in proximity to PrP could be explained by a simple model, thereby providing one of the first glimpses into the determinants that shape the molecular environment of a specific membrane protein.

F) Elucidation of PrP’s cellular role in the polysialylation of the neural cell adhesion molecule 1 (2016).

This project emerged from our earlier study of the evolutionary origins of the prion gene and our successful generation of a first CRISRP-Cas9 PrP knockout cell model. Recognizing that ZIP transporters most closely related to PrP play a critical role in a program known as epithelial to mesenchymal transition (EMT), led us to investigate if PrP inherited an involvement in this morphogenetic program. Indeed, we discovered that PrP levels are massively upregulated during EMT and its presence is essential for the execution of a signaling loop that controls NCAM1 polysialylation. This insight represents a milestone in efforts to reveal PrP’s elusive function.