1. Upregulation of Leucine-rich Repeat Kinase 2 Expression in Sporadic Parkinson Disease involves Specific MicroRNA. LRRK2 has been implicated in the progression of sporadic Parkinson Disease (PD). However, the mechanisms regulating LRRK2 protein expression and function in the brains of patients with sporadic PD remain to be determined. Here we show that the expression of LRRK2 protein is significantly increased in the brains of patients with sporadic PD. Moreover, we found a significant inverse-correlation between the expression of LRRK2 and microRNA-205 (miR-205) in the PD brains. The expression of LRRK2 and miR-205 were also dynamically regulated and inversely correlated in multiple regions of the brain as mice aged, suggesting a potential post-transcriptional regulatory role of miR-205 in modulating LRRK2 expression. Indeed over-expression of miR-205 suppressed the expression of LRRK2 in both cell lines and primary neuronal cultures, as well as rescued the neurite growth defects induced by over-expressing the PD-related LRRK2 R1441G mutation. In summary, we demonstrate that LRRK2 protein is up-regulated in the brains of patients with sporadic PD possibly due to down-regulation of miR-205. Our findings also suggest that over-expression of miR-205 may help to suppress the pathogenic elevation of LRRK2 in the brains of patients with PD. * The utility of miR-205 as a biomarker and therapeutic target has been submitted for patent application. * The manuscript of miR-205 data is under revision by Human Molecular Genetics. 2. LRRK2 as a Modulator of PKA Pathway during Synaptogenesis LRRK2 is actively involved in cytoskeletal dynamics for review (Parisiadou and Cai, 2010). In accordance, a critical connection between LRRK2 and actin dynamics is indicated in the neurite outgrowth during neuron development (Parisiadou et al., 2009). Dendritic spine formation that underlies the basis for neuron connectivity and plasticity in the brain is also critically determined by the actin cytoskeleton (Ethell and Pasquale, 2005;Tada and Sheng, 2006;Schubert and Dotti, 2007). Spine morphogenesis include the transition from initial long, thin, highly flexible filopodia to more stable spines that are considered mature when show characteristic bulbous enlargements at their tips (spine head) and distinct neck (Oray et al., 2006;Yoshihara et al., 2009). The importance of the maintenance of spine morphology and density is reflected by the correlation between abnormal spine properties and brain dysfunction (Kasai et al., 2003). Cofilin, a modulator of actin filament turnover, critically regulates the actin-based dynamics of spine formation (Meng et al., 2002). Cofilin activities are inhibited by LIM kinase-mediated phosphorylation and activated by Slingshot-induced de-phosphorylation on a highly conserved Serine at residue three (S3) (Bernstein and Bamburg, 2010). However, alternative regulatory mechanisms have been described, including a protein kinase A (PKA)-dependent pathway (Paavilainen et al., 2004). PKA-mediated signaling pathways are critical for neuron development and function (Frey et al., 1993;Greenberg et al., 1987;Choi et al., 2002). PKA is a holoenzyme that consists of two regulatory and two catalytic subunits. At resting state, each regulatory subunit binds to a catalytic unit and keeps it inactive. Upon binding with cAMP, the regulatory subunit dissociates with catalytic unit, which then acts to phosphorylate its substrates (Scott, 1991;Francis and Corbin, 1994). The mammalian PKA family could be subdivided into types I and II based on their regulatory subunits (Brandon et al., 1997). The II-beta;regulatory (RII-beta) subunit is highly expressed in neurons (Ventra et al., 1996) (Brandon et al., 1998). PKA spatial intracellular distribution possesses a critical role in PKA signaling since it might contribute to signaling specificity and efficacy (Lu et al., 2007;Zaccoloet al., 2002). The subcellular localization of type II PKA is controlled by the A kinase anchoring proteins (AKAPs) (Wong and Scott, 2004;Zhong et al., 2009). Here we show that LRRK2 is a critical regulator of PKARII-beta's subcellular distribution in neurons, and assign a new role on LRRK2 as a modulator of PKA pathway particularly around postnatal two to three weeks, a critical period for the synapse formation in the mouse brain. LRRK2-absence resulted to increased PKA activity as evidenced by increased phosphorylation of cofilin and AMPA type glutamate receptor subunit GR1A1. The alterations of cofilin and GR1A1 phosphorylation impaired the spine formation and synaptic transmission. Overall, our data reveal a new regulatory role of LRRK2 during synaptogenesis, in which LRRK2 might function as part of the developmental switch imposed onPKA-related pathways.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000944-06
Application #
8736658
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2013
Total Cost
$665,812
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Cho, Hyun Jin; Xie, Chengsong; Cai, Huaibin (2018) AGE-induced neuronal cell death is enhanced in G2019S LRRK2 mutation with increased RAGE expression. Transl Neurodegener 7:1
Guo, Fang; Liu, Xinyao; Cai, Huaibin et al. (2018) Autophagy in neurodegenerative diseases: pathogenesis and therapy. Brain Pathol 28:3-13
Zheng, Meige; Jiao, Luyan; Tang, Xiaolu et al. (2017) Tau haploinsufficiency causes prenatal loss of dopaminergic neurons in the ventral tegmental area and reduction of transcription factor orthodenticle homeobox 2 expression. FASEB J 31:3349-3358
Song, Ruiwen; Li, Jing; Zhang, Jin et al. (2017) Peptides derived from transcription factor EB bind to calcineurin at a similar region as the NFAT-type motif. Biochimie 142:158-167
Zhao, Yane; Zhang, Jin; Shi, Xiaoyu et al. (2016) Quercetin targets the interaction of calcineurin with LxVP-type motifs in immunosuppression. Biochimie 127:50-8
Ma, Bo; Xu, Leyan; Pan, Xiaodong et al. (2016) LRRK2 modulates microglial activity through regulation of chemokine (C-X3-C) receptor 1 -mediated signalling pathways. Hum Mol Genet 25:3515-3523
Ma, Bo; Yu, Jia; Xie, Chengsong et al. (2015) Toll-Like Receptors Promote Mitochondrial Translocation of Nuclear Transcription Factor Nuclear Factor of Activated T-Cells in Prolonged Microglial Activation. J Neurosci 35:10799-814
Liu, Guoxiang; Sgobio, Carmelo; Gu, Xinglong et al. (2015) Selective expression of Parkinson's disease-related Leucine-rich repeat kinase 2 G2019S missense mutation in midbrain dopaminergic neurons impairs dopamine release and dopaminergic gene expression. Hum Mol Genet 24:5299-312
Wandu, Wambui S; Tan, Cuiyan; Ogbeifun, Osato et al. (2015) Leucine-Rich Repeat Kinase 2 (Lrrk2) Deficiency Diminishes the Development of Experimental Autoimmune Uveitis (EAU) and the Adaptive Immune Response. PLoS One 10:e0128906
Cho, Hyun Jin; Yu, Jia; Xie, Chengsong et al. (2014) Leucine-rich repeat kinase 2 regulates Sec16A at ER exit sites to allow ER-Golgi export. EMBO J 33:2314-31

Showing the most recent 10 out of 25 publications