(G2019S) LRRK2 causes early-phase dysfunction of SNpc dopaminergic neurons and impairment of corticostriatal long-term depression in the PD transgenic mouse
Introduction
Patients with familial type 8 of Parkinson's disease (PARK8) exhibit autosomal dominant inheritance and a late-onset loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) (Corti et al., 2011, Hardy et al., 2009, Lees et al., 2009, Martin et al., 2011, Sundal et al., 2012, Wider et al., 2010). Molecular genetic studies identified missense mutations in leucine-rich repeat kinase 2 (LRRK2) as the cause of PARK8 (Paisan-Ruiz et al., 2004, Zimprich et al., 2004). LRRK2 consists of several functional domains, including ankyrin repeat region, leucine-rich repeat (LRR) domain, ROC (Ras of complex proteins) GTPase domain, C-terminal of ROC (COR) domain, kinase domain related to mitogen-activated protein kinase kinase kinase (MAPKKK) and C-terminal WD40 region (Cookson, 2010, Mata et al., 2006). LRRK2 expression is found in brain regions implicated in the neuropathology of Parkinson's disease (PD), such as substantia nigra and caudate putamen (Biskup et al., 2006, Simon-Sanchez et al., 2006, Westerlund et al., 2008).
LRRK2 is the most frequent causative gene in both familial and sporadic PD cases, and PD-associated mutations are found in every domain of LRRK2 (Corti et al., 2011, Hardy et al., 2009, Martin et al., 2011, Mata et al., 2006). Among LRRK2 mutations found in PD patients, the (G2019S) mutation located in the kinase domain is the most common amino acid substitution (Lees et al., 2009, Martin et al., 2011, Mata et al., 2006, Sundal et al., 2012). Based on genetic screening results obtained from different ethnic populations, (G2019S) LRRK2 mutation is the most common genetic cause of both familial and sporadic PD cases (Corti et al., 2011, Kumari and Tan, 2009, Lees et al., 2009, Martin et al., 2011, Sundal et al., 2012). Previous studies by other groups and us demonstrated that LRRK2 induced Ser/Thr phosphorylation and that the (G2019S) mutation augmented LRRK2 kinase activity (Chen et al., 2012, Greggio et al., 2006, Smith et al., 2006, West et al., 2007).
A transgenic mouse expressing mutant (G2019S) LRRK2 is a valuable animal tool to investigate molecular pathogenic mechanism of (G2019S) LRRK2-induced familial or sporadic PD. Consistent with previous neuropathological studies showing that PD patients with the (G2019S) LRRK2 mutation displayed a late-onset loss of SNpc dopaminergic neurons (Giasson et al., 2006, Gilks et al., 2005, Rajput et al., 2006, Wider et al., 2010), (G2019S) LRRK2 transgenic mice prepared by us or Moore and co-workers exhibited a late-phase (> 12-month-old) death of SNpc dopaminergic neurons (Chen et al., 2012, Ramonet et al., 2011). Our study further suggested that the (G2019S) LRRK2 mutation exerted a gain-of-function and enhancing effect on LRRK2 kinase activity, leading to overphosphorylation of MAPK kinase 4 (MKK4) at Ser257, abnormal activation of MKK4–JNK–c-Jun cell death pathway and resulting loss of SNpc dopaminergic neurons in (G2019S) LRRK2 transgenic mice (Chen et al., 2012).
Multiple domains of LRRK2 are involved in regulating a variety of neuronal functions, including signal transduction, synaptic vesicle trafficking, transcription and translation (Belluzzi et al., 2012, Berwick and Harvey, 2011, Daniels et al., 2011, Dorval and Hébert, 2012, Matta et al., 2012, Piccoli et al., 2011). Therefore, LRRK2 is expected to regulate various functions of SNpc dopaminergic neurons. Previous studies using mouse models of several neurodegenerative diseases, including Huntington's disease, spinocerebellar ataxia type 1 and spinocerebellar ataxia type 3, reported that neuronal dysfunction preceded neuronal death (Cepeda et al., 2010, Raymond et al., 2011, Shakkottai et al., 2011, Takafumi et al., 2001). Thus, it is reasonable to hypothesize that prior to a late-phase cell death of SNpc dopaminergic neurons observed in the (G2019S) LRRK2 transgenic mouse (Chen et al., 2012, Ramonet et al., 2011), (G2019S) LRRK2 could also induce an early-phase malfunction of SNpc dopaminergic cells, leading to an impaired function of nigrostriatal dopaminergic system.
One of the most important physiological functions of the nigrostriatal dopaminergic pathway is its involvement in the induction of corticostriatal long-term synaptic plasticity (Calabresi et al., 2007, Kreitzer and Malenka, 2008, Lovinger, 2010, Luscher and Huber, 2010). Synaptic plasticity expressed at corticostriatal glutamatergic synapses of striatal medium spiny neurons requires normal nigrostriatal dopaminergic transmission and plays an important role in physiological functions of the striatum (Calabresi et al., 2007, Lovinger, 2010). In the present study, our results suggest that mutant (G2019S) LRRK2 causes early-phase dysfunctions of SNpc dopaminergic cells, including a reduction in spontaneous firing frequency and a decrease in evoked dopamine release, and impaired induction of corticostriatal long-term depression (LTD) in the PD transgenic mouse.
Section snippets
Generation of transgenic mice expressing mutant (G2019S) LRRK2
As described previously (Chen et al., 2012), transgene construct was prepared by inserting cDNA of HA-tagged mutant (G2019S) LRRK2 into CMV enhancer/platelet-derived growth factor (PDGF)-β chain expression vector. Then, linearized transgene construct was purified and injected into male pronuclei of fertilized oocytes prepared from FVB/N mice, which were then implanted into pseudopregnant mice. Founder transgenic mice were mated with wild-type FVB/N mice and bred into stable transgenic lines.
Eight to nine-month-old (G2019S) LRRK2 transgenic mice display the symptom of hypoactivity in the absence of a significant degeneration of the nigrostriatal dopaminergic pathway
In our previous study (Chen et al., 2012), we have successfully prepared a PD animal model by generating transgenic mice expressing disease-causing (G2019S) LRRK2. Double immunofluorescence staining demonstrated the expression of (G2019S) LRRK2 in SNpc TH-positive dopaminergic neurons of (G2019S) LRRK2 transgenic mice (Chen et al., 2012). Twelve to sixteen month-old (G2019S) LRRK2 mice prepared by us exhibited progressive neuronal death of SNpc TH-positive dopaminergic cells (Chen et al., 2012
Discussion
LRRK2 is the most common causative gene in both familial and sporadic PD patients (Corti et al., 2011, Hardy et al., 2009, Martin et al., 2011, Mata et al., 2006). Among LRRK2 mutations found in PD cases, G2019S is the most frequent amino acid mutation (Lees et al., 2009, Martin et al., 2011, Mata et al., 2006, Sundal et al., 2012). A transgenic mouse expressing disease-causing (G2019S) LRRK2 is a valuable tool to study the molecular pathogenic mechanism of mutant (G2019S) LRRK2-induced
Acknowledgments
This work was supported by the National Science Council of ROC (NSC100-2321-B-182-008 and NSC101-2321-B-182-004), Chang Gung Medical Research Projects (CMRPD180433, CMRPD170403, CMRPD1C0621, CMRPD1C0691 and CMRPD1B0331) and Healthy Aging Research Center of Chang Gung University (EMRPD1D0231).
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These authors contributed equally to this work.