Advisory Committee Chair
Andrew B West
Advisory Committee Members
Rita Cowell
David Standaert
Erik Roberson
Talene Yacoubian
Thomas Von Groen
Document Type
Dissertation
Date of Award
2018
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Two pathological hallmarks define Parkinson disease (PD) including dopaminergic neurodegeneration in substantia nigra pars compacta (SNpc) and accumulation of α-synuclein insoluble inclusions, called Lewy pathology, in surviving neurons. LRRK2 (encoding Leucine-rich repeat kinase 2) and SNCA (encoding α-synuclein (α-syn)) are two major genes linked to PD. Pathogenic mutations in these two genes cause autosomal dominant (AD) PD. Additionally, genetic variations in LRRK2 and SNCA are associated with increased risk of sporadic PD. Cellular and animal studies using preformed α-syn fibrils (PFF) demonstrate that the fibrils can be internalized by neurons and act as seeds that can recruit and corrupt endogenously expressed α-syn. Past studies injected the PFF at the striatum because it is the main input of basal ganglia and rich in presynaptic terminals, providing a high pool of endogenous α-syn. Here, we demonstrate that injection of PFF at the cell bodies of DA neurons in SNpc produce neurodegeneration and α-syn inclusions in both DA neurons and receptive dorsal striatum medium spiny neurons. Additionally, we found that DA neurodegeneration is positively correlated with α-syn inclusions burden at SNpc and dorsal striatum. LRRK2 protein is a multidomain protein with dual enzymatic domains, ROC domain that has GTPase activity and kinase domain that has kinase activity. Pathogenic mutations of LRRK2 are clustered in the enzymatic domains and are associated with 2-3 folds increase in the kinase activity. Expression studies showed that LRRK2 is highly expressed in neurons and myeloid cells (non-lymphocytic leukocytes). However, therapeutic potentials of LRRK2 kinase inhibitors and the role of LRRK2 in innate immune response are not clear. Here, we demonstrate that LRRK2 kinase inhibition using PF-475 drug block rAAV2-α-syn induced neurodegeneration and neuroinflammation. Also, PF-475 is well-tolerated in rats with no significant pathological changes in organs expressing LRRK2 such as liver, lung, and kidney. Furthermore, using a CX3CR1-CreERT2 genetic system that can fate mapping microglia, we found that LRRK2 is upregulated in monocyte-derived macrophages but not microglia in response to INFγ-induced neuroinflammation, and that inhibition of LRRK2 kinase blocked the recruitment of MDM into brain parenchyma in neuroinflammation.
Recommended Citation
Abdelmotilib, Hisham, "Mechanisms Of Leucine-Rich Repeat Kinase 2 And Alphα-Synuclein In Pathogenesis Of Parkinson Disease" (2018). All ETDs from UAB. 947.
https://digitalcommons.library.uab.edu/etd-collection/947