Joel Watts

I obtained my BSc in Biochemistry from the University of Western Ontario in 2003 and my graduate studies were conducted in the lab of Dr. David Westaway at the University of Toronto. My graduate work involved the first characterization of the novel prion protein family member Shadoo. After receiving my PhD in 2008 I pursued postdoctoral studies in the lab of Nobel Laureate Dr. Stanley Prusiner at the University of California San Francisco. My postdoctoral work focused on developing new transgenic mouse models of prion disease as well as exploring the prion-like properties of Aβ and α-synuclein, which are implicated in the pathobiology of Alzheimer’s disease and Parkinson’s disease, respectively. In 2014 I started my own lab at the Tanz Centre for Research in Neurodegenerative Diseases with a cross-appointment within the Department of Biochemistry.

My research interests include the prion diseases and related human neurodegenerative disorders such as Alzheimer’s disease. My research focuses on developing improved mouse and cellular models of human neurodegenerative diseases that can be used to study the biology of these illnesses and as tools for developing novel therapeutics.

Protein Misfolding and Neurodegenerative Diseases

Protein misfolding is at the root of many neurodegenerative diseases of ageing, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Creutzfeldt-Jakob disease (CJD). These are diseases of protein conformation: the misfolding and subsequent aggregation of proteins or peptides into β-sheet-enriched forms initiates a cascade of events that ultimately leads to neurological dysfunction and death of neurons or glial cells in the brain. My lab focuses on understanding the molecular details of protein aggregation with an emphasis on designing accurate animal models of protein misfolding diseases.

Investigating the Mechanisms of Prion Formation and Toxicity

Prions are infectious proteins that cause rare but invariably fatal neurodegenerative illnesses such as CJD in humans, chronic wasting disease in deer, and bovine spongiform encephalopathy (also known as “mad cow disease”). These diseases are caused by the accumulation of misfolded prion protein (PrP) in the brain. PrP can exist in two distinct conformational states: PrPC, which is the properly folded cellular version of the protein, and PrPSc, which is the misfolded and infectious conformational isoform.

We are interested in exploiting the unique properties of the prion protein from the bank vole (Myodes glareolus) in order to gain insight into the biology of prion disease. Unlike other animals, bank voles are susceptible to prions from many different species. We recently demonstrated that transgenic mice engineered to express bank vole PrP (BVPrP) are also highly susceptible to prions from various species, suggesting that BVPrP may be a “universal acceptor” for prions. Remarkably, these mice also develop a spontaneous, transmissible neurodegenerative disease. Thus, BVPrP appears to be much more prone to misfolding than PrPs from other species.

We are currently using BVPrP-expressing transgenic and knock-in mice to study the factors that govern spontaneous prion formation in the brain and to isolate candidate neurotoxic and self-propagating PrP assemblies, which may ultimately lead to new therapeutic strategies for halting the spread of prions in the brain.

The Expanding Universe of Prion Diseases

An emerging theory is that the progressive nature of many neurodegenerative diseases, including AD and PD, stems from the formation and subsequent spread of self-propagating, prion-like protein aggregates throughout the brain. This occurs when misfolded, aggregated proteins attain the ability to template the misfolding of their properly folded counterparts, enabling the prion-like “propagation” of the misfolded form. As with prions, intracerebral injection of susceptible transgenic mice with α-synuclein aggregates accelerates disease and induces the deposition of α-synuclein in the brain. Similarly, inoculation of susceptible transgenic mice with aggregated Aβ peptide induces the formation of amyloid plaques similar to those found in the brains of AD patients.

Lab Research Interests

My lab is interesting in exploring the following questions:

1.     Are different “strains” of Aβ or α-synuclein aggregates responsible for the diverse clinical and pathological presentations of disease in humans?
2.     What is the biochemical nature of the specific Aβ and α-synuclein assemblies that mediate spreading of protein aggregation during disease?
3.     Can we take advantage of the prion-like behaviour of Aβ and α-synuclein aggregates in order to develop superior, more translational mouse models of human neurodegenerative diseases?

Appointments, Cross Affiliations, Memberships

Tanz Centre for Research in Neurodegenerative Diseases

Courses Taught

BCH2103H Current Topics in Prion Biology
BCH473Y Advanced Research Project in Biochemistry
BCH242Y Introduction to Biochemistry
LMP410H1 Pathobiology of Neurodegenerative Disease

Awards and Distinctions

2017-2027 — Canada Research Chair in Protein Misfolding Disorders
2017-2022 — Ontario Early Researcher Award
2015-2017 — CIHR New Investigator Award
2012-2013 — NIH K99/R00 Pathway to Independence Award
2008-2011 — CIHR Postdoctoral Fellowship
2005-2007 — NSERC Postgraduate Scholarship
2003-2005 — NSERC Postgraduate Scholarship