Research Description

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: PrP^C, which is the properly folded cellular version of the protein, and PrP^Sc, which is the misfolded and infectious conformational isoform.

Tg(BVPrP) mice develop a spontaneous neurodegenerative disease that recapitulates all the pathological hallmarks of prion disease in rodents.

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 these BVPrP-expressing transgenic 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.

Prion-like induction of protein aggregation in the brains of transgenic mice.

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?

Publications

View all publications on PubMed

Aβ43 aggregates exhibit enhanced prion-like seeding activity in mice
Ruiz-Riquelme A, Mao A, Barghash MM, Lau HHC, Stuart E, Kovacs GG, Nilsson KPR, Fraser PE, Schmitt-Ulms G, Watts JC
Acta Neuropathologica Communications 2021 9(1): 83.  Read

α-Synuclein strains target distinct brain regions and cell types
Lau A, So RWL, Lau HHC, Sang JC, Ruiz-Riquelme A, Fleck SC, Stuart E, Menon S, Visanji NP, Meisl G, Faidi R, Marano MM, Schmitt-Ulms C, Wang Z, Fraser PE, Tandon A, Hyman BT, Wille H, Ingelsson M, Klenerman D, Watts JC
Nature Neuroscience 2020 23(1): 21-31.  Read

Engineering a murine cell line for the stable propagation of hamster prions
Bourkas MEC, Arshad H, Al-Azzawi ZAM, Halgas O, Shikiya RA, Mehrabian M, Schmitt-Ulms G, Bartz JC, Watts JC
Journal of Biological Chemistry 2019 294(13): 4911-4923.  Read

Prion-like propagation of β-amyloid aggregates in the absence of APP overexpression
Ruiz-Riquelme A, Lau HHC, Stuart E, Goczi AN, Wang Z, Schmitt-Ulms G, Watts JC
Acta Neuropathologica Communications 2018 6(1): 26.  Read

Towards authentic transgenic mouse models of heritable PrP prion diseases
Watts JC, Giles K, Bourkas MEC, Patel S, Oehler A, Gavidia M, Bhardwaj S, Lee J, Prusiner SB
Acta Neuropathologica 2016 132(4): 593-610.  Read

Serial propagation of distinct strains of Aβ prions from Alzheimer’s disease patients
Watts JC, Condello C, Stöhr J, Oehler A, Lee J, DeArmond SJ, Lannfelt L, Ingelsson M, Giles K, Prusiner SB
PNAS 2014 111(28): 10323-10328.  Read

Evidence that bank vole PrP is a universal acceptor for prions
Watts JC, Giles K, Patel S, Oehler A, DeArmond SJ, Prusiner SB
PLoS Pathogens 2014 10(4): e1003990.  Read

Transmission of multiple system atrophy prions to transgenic mice
Watts JC, Giles K, Oehler A, Middleton LT, Dexter DT, Gentleman SM, DeArmond SJ, Prusiner SB
PNAS 2013 110(48): 19555-19560.  Read

Purified and synthetic Alzheimer’s amyloid beta (Aβ) prions
Stöhr J*, Watts JC*, Mensinger ZL, Oehler A, Grillo SK, DeArmond SJ, Prusiner SB, Giles K *Equal contribution
PNAS 2012 109(27): 11025-11030.  Read

Spontaneous generation of rapidly transmissible prions in transgenic mice expressing wild-type bank vole prion protein
Watts JC, Giles K, Stöhr J, Oehler A, Bhardwaj S, Grillo SK, Patel S, DeArmond SJ, Prusiner SB
PNAS 2012 109(9): 3498-3503.  Read