Research Activities
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.