Parkinson disease (PD) is a neurodegenerative disease that directly affects over 100,000 Canadians and over 1,000,000 people in North America. No cause-directed therapies have been developed since the discovery of dopamine deficiency in PD brains by Dr. Oleh Hornykiewicz in 1961. Presently available therapies do not change the course of PD, do not treat its many non-motoric symptoms, and do not address the root causes of parkinsonism. The failure to deliver new, cause-directed therapies is rooted in the lack of breakthroughs in our understanding of both the fundamental causes of the disease and the underlying molecular mechanism(s) through which they destroy dopaminergic and other neurons to cause neurodegeneration.  

The goal of our research is to address these issues from several directions:  

1. We seek to contribute to the development of cause-directed therapies. In doing so, we are focusing on the molecular processes that drive neurodegeneration. Specifically, we are studying the mechanisms by which PD-linked genes (including alpha-synuclein, Parkin, LRRK2 and GBA1) lead to neuronal dysfunction. Of note, we were the first neuroscience team to identify a role for LRRK2 in the immune system in 2011; we also co-discovered biochemical links between lysosomal dysfunction, including those caused by mutations in two enzymes, GBA1 and cathepsin D, and altered alpha-synuclein metabolism in mammalian brain.  

2. We are developing better informed animal models of young-onset parkinsonism and late-onset PD as well as dementia with Lewy bodies (DLB), which in addition to providing valuable insights into disease processes will serve as platforms for pre-clinical testing of PD-targeted therapeutics. This has become a major focus of the laboratory. The latter is pursued in part through partnerships with our academic colleagues here in Ottawa and industry collaborators.  

3. One of the three main focuses of our research is the role of PD-linked genes in the immune system, and brain health downstream of systemic infections. Mutations in LRRK2 are found in >1% of persons with typical, late-onset PD. In addition, SNPs at the LRRK2 locus also associated with altered risk for Crohn’s disease and leprosy, two chronic, inflammatory diseases. We have found that LRRK2 is highly expressed in the immune system, and we hypothesize that its role in immune function is what links these three, otherwise seemingly unrelated diseases.

This is the central theme of a CIHR-funded team effort led by Dr. Schlossmacher and Dr. David Park of the uOttawa Brain & Mind Research Institute. This CIHR Team grant unites Canadian researches at 5 universities with expertise in neuroscience, genetics and molecular immunology from the Parkinson’s-, Crohn’s and leprosy fields. Together, they collaboratively study LRRK2’s function in the immune system (referred to as CLINT Consortium: Canadian LRRK2 in Inflammation Team). Senior members include Drs. Dana Philpott (U Toronto), Erwin Schurr (McGill), John D. Rioux (U Montreal), Shawn Hayley (Carleton U), Derrick Gibbings, Earl Brown, D. Park and M. Schlossmacher (uOttawa).  

4. Creating new tools for Parkin research: A challenge in the field of Parkin research is the lack of antibodies to study the protein in human brain tissue. With the support of the Michael J. Fox Foundation, we are collaborating with BioLegend’s Dr. Peggy Taylor (Dedham, MA.; USA) to create new immunological tools that enable advances in Parkin research.  

5. Prediction modeling: Based on multiple prediction algorithms in clinical medicine and available knowledge in the field of PD epidemiology, we hypothesized that it would be possible to predict the incidence rate of PD in neurologically healthy subjects. In collaboration with Drs. Tiago Mestre (Division of Neurology) and Doug Manuel (Methods Centre), we recently published a first draft for the “PREDIGT Score” model (Schlossmacher et al., 2017). We are continuing and expanding this collaboration for the necessary validation of a still theoretical algorithm by using data from 5 large PD cohorts.