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Funded Studies

Effect of LRRK2 Mutations on PD-associated Inflammation

Objective/Rationale:
Increased inflammation is associated with the progression and possibly even onset of Parkinson’s disease (PD). Mutations in the LRRK2 gene are also associated with PD, and recent evidence points to a role for LRRK2 to modulate inflammatory pathways. This project aims to investigate inflammatory cytokines (small proteins involved in cell signaling) in people with LRRK2 mutations who have and who do not have PD. Outcomes will provide more information on the role of inflammation in PD. 

Project Description:
Serum and cerebrospinal fluid samples will be obtained from the LRRK2 Cohort Consortium through The Michael J. Fox Foundation. Inflammatory cytokines will be measured by ELISA (a test that uses antibodies and color change to identify a substance). Statistical analysis will be used to see how changes in inflammatory cytokines relate to clinical measures of PD in LRRK2 mutation carriers with and without PD.

Relevance to Diagnosis/Treatment of Parkinson’s Disease: 
The results of this study could provide more information regarding the utility of anti-inflammatory drugs for the treatment of Parkinson’s disease. Results will also provide information about how LRRK2 mutations influence the inflammatory response in PD. 

Anticipated Outcome:
We anticipate that increased inflammatory cytokines will be associated with a number of clinical signs or measures of PD. If increased inflammation is associated with early signs/symptoms of PD, then this will provide more evidence of a role for inflammation in PD progression. The identification of early markers of PD is crucial for efficient therapeutic intervention.

Final Outcome

Leucine-rich repeat kinase 2 (LRRK2) is the greatest known genetic contributor to Parkinson's disease (PD).
Recent research implicated LRRK2 in inflammation. Our aim in this study was to investigate inflammatory markers -- molecules involved in inflammation -- in people with LRRK2 mutations -- genetic changes that render this protein dysfunctional -- who have and who do not have PD. We expected the results of this study to further clarify the role of inflammation in PD.

First, we measured several inflammatory markers in the blood of people carrying the G2019S mutation in the LRRK2 gene who do not have Parkinson's disease (PD) symptoms. Then, we compared their marker levels to the levels in healthy people. We also compared the inflammatory markers in the blood of people with and without the LRRK2 G2019S mutation, all of whom have been diagnosed with PD. We found that several inflammatory markers were elevated in the blood of people without symptoms carrying the mutation. This suggests that inflammation outside the brain may represent an early sign of Parkinson's disease; however, further studies are needed to determine if people with the highest levels of inflammation are indeed more likely to develop PD. In people already diagnosed with Parkinson's, the inflammatory markers were similar to those of people with the LRKK2 mutation without symptoms. People carrying the LRRK2 G2019S mutation with and without symptoms had slight differences in the inflammatory profile, specifically, in the growth factor proteins associated with inflammation.

June 2016

Presentations:
Oral presentation at the International Society for Neurochemistry meeting (Cairns, Australia, 2015).
Oral presentation at the Garvan Institute of Medical Research International Fellow Symposium on inflammation in disease (Sydney, Australia, 2015).
Oral presentation at the Biochemical Society LRRK2: ten years along the road to therapeutic intervention meeting (London, UK, 2016).

Publications:
Dzamko N, Rowe DB, Halliday GM. Increased peripheral inflammation in asymptomatic leucine-rich repeat kinase 2 mutation carriers. Mov Disord. 2016;31(6):889-897.


Researchers

  • Nicolas Dzamko, PhD

    Sydney Australia


  • Glenda Margaret Halliday, PhD

    Sydney Australia


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