Investigating Roles of LRRK2: Neurite Outgrowth and Filopodia in Midbrain Dopamine Primary Neurons
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1
Mayo Clinic, Department of Neuroscience, United States
Amongst several currently identified genes that contribute to Parkinson’s disease (PD), mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are the most commonly known cause of autosomal dominant PD. LRRK2 encodes a multi-domain protein consisting of a leucine-rich repeat domain, Ras in complex proteins (ROC) domain, C-terminal of ROC (COR) domain, a kinase domain related to mitogen-activated protein kinase kinase kinases (MAPKKKs) and a WD40 protein interaction domain. The G2019S mutation in the kinase domain is the most prevalent mutation in LRRK2 in both familial and sporadic cases. Current literature suggests this is a gain-of-function mutation resulting in higher kinase activity.
Using LRRK2 G2019S Knock In (KI) mice and murine LRRK2 Knock Out (KO) mice, we investigated the role of endogenous Lrrk2 and the effect of the G2019S mutation on neurite outgrowth in tyrosine-hydroxylase positive midbrain primary cultures. We observed an increase in total neurite outgrowth in KO midbrain dopamine neurons compared to those from their heterozygous (HT) littermates possessing one copy of the LRRK2 gene. In KI primary cultures however we observed no difference in neurite outgrowth between homozygous KI and wild-type (WT) midbrain dopamine neurons.
A study of the more subtle phenotype of dendritic filopodia in primary cultures showed an increase in the number of filopodia in KO midbrain dopamine neurons compared to WT neurons, whilst KI cultures exhibited a decrease in filopodia numbers compared to WT neurons. These studies suggest that regulation of dendritic filopodia and branches is an inherent function of Lrrk2. Further, these studies support that a pathogenic mutation in Lrrk2 increases this negative regulation of process and filopodia formation, lending support to the idea that this is a gain of function mutation.
Conference:
2010 South East Nerve Net (SENN) and Georgia/South Carolina Neuroscience Consortium (GASCNC) conferences, Atlanta , United States, 5 Mar - 7 Mar, 2010.
Presentation Type:
Poster Presentation
Topic:
Posters
Citation:
Beevers
JE,
Behrouz
B,
Daechsel
JC,
Yue
M,
Melrose
HL and
Farrer
MJ
(2010). Investigating Roles of LRRK2: Neurite Outgrowth and Filopodia in Midbrain Dopamine Primary Neurons.
Front. Neurosci.
Conference Abstract:
2010 South East Nerve Net (SENN) and Georgia/South Carolina Neuroscience Consortium (GASCNC) conferences.
doi: 10.3389/conf.fnins.2010.04.00026
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Received:
16 Mar 2010;
Published Online:
16 Mar 2010.
*
Correspondence:
Joel E Beevers, Mayo Clinic, Department of Neuroscience, Kista, United States, beevers.joel@mayo.edu