Dr. Neil Cashman

Professor of Medicine, University of British Columbia
Researcher of the month: 
Apr 2012

The Prion Hypothesis Kick-starts Scientific Inquiry

Dr. Neil Cashman, a clinical neurologist and neuroscientist at the Brain Research Centre, University of British Columbia (UBC), first became aware of the prion hypothesis while reading a 1982 article by Stanley Prusiner in Science. This “completely novel and weird form of infectivity” captivated his curiosity.

Driven by his clinical experiences with patients suffering from incurable neurodegenerative diseases, he became intrigued by the possibility that misfolded proteins, which exhibit structural changes at the molecular level that impact protein function, might “seed” certain neurodegenerative diseases – much like viruses cause the flu.

Misfolded proteins, referred to as prion-like, prompt the misfolding of normal proteins in the absence of nucleic acids – triggering the propagation of a pathological process within the nervous system.

Dr. Cashman, a Tier 1 Canada Research Chair at UBC in Neurodegeneration and Protein Misfolding Diseases, is the Scientific Director of PrioNet Canada, a Centre of Excellence Network for research into prions and prion diseases in humans and animals. Dr. Cashman co-founded Amorfix Life Sciences, a Toronto-based biotech company, to translate laboratory discoveries into therapies for human disease. He won the Jonas Salk prize for “a lifetime of outstanding contributions to basic biomedical research” in 2000 and was elected to the Canadian Academy of Health Sciences in 2008. He has just received the Genome BC Award for Scientific Excellence. He is also the Academic Director of the Vancouver Coastal Hospital ALS Centre.

A personal crusade

As a clinician, Dr. Cashman has spent his professional life trying to ease the suffering of individuals stricken with neurodegenerative diseases such as Creutzfeldt-Jakob disease (CJD), amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease), and Alzheimer’s disease (AD).

“I’ve been moved and challenged by my experiences as a neurologist working in neurodegenerative diseases, especially in ALS but also in Alzheimer’s disease and other degenerative diseases,” he says. “I work with people and their families who are courageous and full of integrity in the face of progressive, fatal diseases. That’s something that has driven me professionally for decades.”

For more than 20 years, Dr. Cashman’s research has focused on the role of propagated misfolding of proteins in disease, and on treatments aimed at blocking this process in these devastating conditions. His laboratory is working on therapeutics for ALS and AD, applying hard-earned lessons from years of painstaking research to develop therapies, diagnostics, and preventive vaccines.

Eureka moments

The prion hypothesis began as a scientific explanation for what happens in infectious, transmissible and fatal neurodegenerative diseases, such as bovine spongiform encephalopathy (BSE or mad cow disease) and CJD.

In the late 1990s, Dr. Cashman hypothesized that the prion protein, implicated in BSE and CJD, exposes different parts of its molecular structure than normal proteins. After about 5 years of dogged effort, his laboratory found just such a region – a tyrosine-tyrosine-arginine (YYR) motif. Buried deep inside normal prion proteins, this region was exposed on the surface of diseased prion protein. The research was published in Nature Medicine in 2003 and cited as a research milestone by the Canadian Institutes for Health Research (CIHR).

The YYR region was an immunological epitope, a portion of a molecule to which antibodies could bind. Lab-grown monoclonal antibodies were able to neutralize the infectious prion proteins, in much the same way that human antibodies combat viruses. Native proteins were untouched.

“That discovery was gratifying, to say the least,” says Dr. Cashman. Its potential therapeutic implications are vast. 

A second eureka moment in his career arose from a desire to apply this knowledge to ALS. He formulated the hypothesis that the misfolding of superoxide dismutase-1 (SOD1), a protein implicated in ALS, may contribute to neurodegeneration.

“I had to systematically identify the parts of SOD1 that were exposed when the protein was misfolded in disease,” he explains. “We found the first such epitope, which we published in Nature Medicine, and then the second, published in Proceedings of the National Academy of Sciences (PNAS). That was the beginning of understanding how SOD1 misfolds in ALS.”

In the pivotal paper in PNAS, his team, in collaboration with colleagues from the University of Alberta, demonstrated that SOD1 has prion-like properties. The misfolded protein coerces native SOD1 to change shape. Misfolded SOD1 accumulates in large complexes, much like prion proteins in BSE.

These findings provide a molecular explanation for the progressive spread of ALS. PrioNet Canada, Amorfix Life Sciences, and CIHR contributed financial support to this research.

But the work didn’t stop there. “We stained ALS tissue for misfolded SOD1, and found it. We then tested a (monoclonal) antibody against the epitope in a mouse model of ALS and discovered that it was effective in delaying disease,” he explains.

Biogen-Idec Corporation has licensed this discovery for development and is now in the pre-clinical phase of designing an immunotherapy for ALS.

“We started with a novel hypothesis that a prion-like protein might be the cause of ALS and that, if indeed there was one, it was likely to be SOD1. Then we identified and validated certain epitopes in SOD1 as therapeutic targets. That was exciting and amazing,” says Dr. Cashman.

Targeting AD

Dr. Cashman and his team are now trying to develop an immunotherapy for AD, based on a specific immune recognition of an epitope on amyloid-beta (Aβ) oligomer, a protein found in brain plaques in AD. These inert plaques are repositories for Aβ oligomers, which are toxic to nerve cells.

“Again, this is a kind of structural dreaming about a region of Aβ oligomers that must be not only exposed but configured in a rigid form easily recognized by antibodies,” he says.

His ambitious long-term goal is to develop a vaccine that will ward off AD. It would neutralize the toxicity of Aβ oligomers and slow or stop the progression of neurodegeneration. Dr. Cashman and his team have begun the work of developing these immunotherapies in collaboration with Cangene Corporation.