Study Rationale:
The levels of alpha-synuclein aggregates and their spreading to different brain region seem to correlate with Parkinson’s disease (PD) progression and symptoms. Increasing evidence suggest that these aggregates are more complex and diverse than we thought and that this complexity and diversity may not be captured by the existing tools (antibodies) used to 1) investigate how they form; 2) explore their role in PD; and 3) correlate their levels in the brain with disease progression and the clinical heterogeneity of PD.
Hypothesis:
We hypothesize that using an expanded toolbox of well-characterized and validated antibodies would enable us to capture the diversity of alpha-synuclein pathology in the brain (i.e., synaptic, glial, etc.), and of alternative progression patterns.
Study Design:
We will examine brain tissue from people with Parkinson’s or Lewy body dementia concentrating on regions implicated in the pathological progression of PD but also examining other regions (e.g., striatum and basal forebrain nuclei).
We also will reassess alpha-synuclein species and pathology in LRRK2 mutation carriers without Lewy bodies using our expanded panel of validated antibodies. We will concentrate generally on the same brain regions.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
A successful project will lead to the identification and validation of antibodies that capture the diversity of the disease pathology. Such tools could facilitate the development of measurement agents for noninvasive monitoring of pathology formation in the brain as biomarker for early detection, monitoring of disease progression and assessing the efficacy of new treatments and disease-modifying strategies.
Next Steps for Development:
The next step would be applying the validated tools to understand the diversity of alpha-synuclein pathology in other neurodegenerative diseases caused by alpha-synuclein aggregation (synucleinopathies). Another avenue would be to determine if the clinical heterogeneity of PD could be explained by the heterogeneity of alpha-synuclein pathology in the brain.