Promising Outcomes of Original Grant:
With previous funding from MJFF, we established the largest collection of clinically characterized autopsies from Parkinson's patients with a LRRK2 mutation, from 16 centers from around the world. We analyzed the pathological features in the brains of these LRRK2 Parkinson's cases and confirmed that they can be different from Parkinson's with an unknown cause (i.e., idiopathic). We found that the pathology in LRRK2 Parkinson's falls into three distinct categories based on the presence of various toxic proteins: 1) pure alpha-synuclein, 2) alpha-synuclein combined with beta-amyloid, tau, and/or TDP-43, and 3) beta-amyloid, tau, and/or TDP-43 with no alpha-synuclein.
Objectives for Supplemental Investigation:
To build on our work, we will explore additional genetic contributors to LRRK2 Parkinson's pathology by examining whether mutations in genes other than LRRK2 are related to the alpha-synuclein, beta-amyloid, tau, and TDP-43 pathologies we observed. We will also compare the pathological features of LRRK2 Parkinson's to idiopathic cases (including Rab10) to determine which features occur in both types.
Importance of This Research for the Development of a New PD Therapy:
Our study will provide important insights about whether LRRK2 and idiopathic Parkinson's are the same at the pathological level. The findings from our study will inform ongoing efforts to develop disease-modifying therapies targeting LRRK2 mutations or alpha-synuclein pathology, which may benefit those with LRRK2 and idiopathic Parkinson's.