Leasure Hall, Room 13
Thursday, March 24, 2016
4:00 P.M.
Coffee and Cookies
Leasure Hall, Room 13 alcove
3:45 P.M.
iochemistry
olecular
iophysics
Molecular underpinnings of Parkinson's disease:
a path to new therapies
Yulan Xiong
Anatomy and Physiology
College of Veterinary Medicine
Kansas State University
Parkinson’s disease (PD) is the most common movement disorder characterized by a progressive loss of
dopaminergic neurons in substantia nigra pars compacta (SNpc). While the majority of PD cases are
sporadic, investigations in the past decade have led to the identification of a number of genes linked to
familial forms of PD, including a newly identified gene known as leucine-rich repeat kinase 2 (LRRK2).
Mutations in the LRRK2 gene are the most common genetic causes of PD so far, and more importantly
these mutations also play important roles in sporadic PD. However, the mechanism underlying LRRK2induced neuronal toxicity is poorly understood. To explore the pathobiology of LRRK2, utilizing a variety
of novel model systems we developed including primary and human neuronal cultures, yeast, Drosophila
and mice, for the first time, we revealed that the GTPase activity plays a key role on the pathobiology of
LRRK2. Inspired by this novel finding, we further identified human ArfGAP1 as a GTPase activating
protein (GAP) for LRRK2 and a potential guanine exchange factor (GEF) for LRRK2. More excitingly, based
on those findings, we developed a novel and robust LRRK2 transgenic mouse model with a progressive
loss of dopaminergic neurons in SNpc associated with behavioral defects, recapitulating the
pathogenesis of PD. Our studies suggest that agents targeting toward regulation of LRRK2 function might
be therapeutic applications for the treatment of PD. The variety of novel model systems we developed
will be valuable not only for LRRK2 study but also for PD field.