Study Rationale:
Lewy bodies are aggregates of protein composed primarily of alpha-synuclein. For a century, Lewy bodies in the brain have been known to be a defining pathological feature of Parkinson's disease (PD). These protein aggregates are thought to be responsible for the death of brain cells and thereby lead to clinical symptoms in PD. Yet, the role of Lewy bodies in PD has been challenged with the discovery that they are absent in certain genetic forms of PD, including PD due to mutations in the LRRK2 gene.
Hypothesis:
We propose that pathological features distinct from Lewy bodies are important contributors to the clinical manifestations of LRRK2-related PD.
Study Design:
We will perform pathological analyses of a series of LRRK2 cases to precisely define features that are related to clinical symptoms, including assessments for protein aggregates that are not Lewy bodies (e.g., beta-amyloid plaques, neurofibrillary tangles and TDP-43 aggregates) and for other forms of alpha-synuclein aggregates that are not Lewy bodies.
Impact on Diagnosis/Treatment of Parkinson's Disease:
This research will characterize the pathology of LRRK2-related PD and identify previously unknown correlates between pathological features and clinical symptoms in this genetic form of PD. Since emerging evidence suggests a role for LRRK2 in sporadic PD, our findings will have the potential for broader implications for PD.
Next Steps for Development:
The outcome of this project could lead to important changes in how we define the pathological features of PD and even how we diagnose the disease.