Advisory Committee Chair
Andrew B West
Advisory Committee Members
David G Standaert
Erik D Roberson
Mark J Suto
James A Mobley
Document Type
Dissertation
Date of Award
2016
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Parkinson disease (PD) is the most common neurodegenerative movement disorder for which no treatments exist capable of slowing progression of the disease. One obstacle slowing the development of novel therapies is the lack of molecular biomarkers for PD prognosis, tracking of disease progression, and assessing efficacious target engagement of compounds that do reach clinical trials. Missense mutations in LRRK2 account for between 1-5% of late onset PD and lead to increases in LRRK2 kinase activity and LRRK2 autophosphorylation. This thesis characterizes the secretion of LRRK2 into extracellularly secreted microvesicles called exosomes. We find that kinase-active LRRK2 is secreted within exosomes and autophosphorylated at the Ser-1292 residue of the protein. Autophosphorylation at this residue is detectable with new antibodies generated against this residue in LRRK2 that is secreted in urinary exosomes of patients. Autophosphorylation at this residue distinguishes PD patients with the G2019S LRRK2 mutation from both G2019S negative patients as well as G2019S positive patients who have yet to manifest disease. These findings suggest Ser(P)-1292 LRRK2 levels may serve as a trait and state biomarker for G2019S positive PD. Levels of autophosphorylation at this residue also correlate with measures of severity for non-motor aspects of disease in idiopathic PD populations and may track longitudinally with disease or development of non-motor impairment. Monitoring phosphorylation at this residue may provide novel biomarkers for LRRK2 inhibitor engagement in clinical trials, tracking PD progression clinically and as an endpoint in clinical trials, and as a state biomarker in patients whom are positive for the G2019S LRRK2 mutation. These findings have provided concrete evidence for a connection between the LRRK2 protein and idiopathic PD and given new insight into the role of LRRK2 in PD pathogenesis.
Recommended Citation
Fraser, Kyle Bradley, "Novel Biomarkers for Parkinson Disease" (2016). All ETDs from UAB. 1665.
https://digitalcommons.library.uab.edu/etd-collection/1665