**2.2 Clinical and neuropathological features of LRRK2 parkinsonism**

The overall clinical profile in individuals with LRRK2 mutations is similar to that of typical late-onset PD (Aasly et al., 2005; Djaldetti et al., 2008; Healy et al., 2008). In agreement with observations in idiopathic PD, individuals with LRRK2-parkinsonism are generally responsive to levodopa treatment. While tremor, bradykinesia, and rigidity occurs in individuals with idiopathic PD, tremor is more frequently observed in individuals with LRRK2 G2019S (Djaldetti et al., 2008; Healy et al., 2008; Hulihan et al., 2008).

Disease duration, severity and response to treatment do not differ between G2019S carriers, regardless of zygosity (Ishihara et al., 2007, (Djaldetti et al., 2008) Individuals harboring LRRK2 G2019S present with similar non-motor features to idiopathic PD with the exception of a lower rate of cognitive impairment and hyposmia (Healy et al., 2008; Hulihan et al., 2008). Remarkably, there are aged G2019S carriers that escape disease (Carmine Belin et al., 2006; Kay et al., 2005). The LRRK2 G2019S mutation is primarily associated with transitional or brainstem Lewy body pathology, reminiscent of typical, late-onset idiopathic PD (Ross et al., 2006). LRRK2 mutation carriers presenting with tauopathy or ubiquitin-positive inclusions, with nigral neuronal loss and gliosis, have also been described (Wszolek et al., 2004; Dachsel et al., 2007; Rajput et al., 2006) Neuropathologic studies of affected individuals from other PARK8-linked kindreds, including Family A (Y1699C), Family D (R1441C), and the Sagamihara family (I2020T) have presented with pleomorphic pathology, including neuronal loss without co-existing pathology or with α-synuclein, ubiquitin-positive inclusions or tau pathology (Taylor et al., 2006).

#### **2.2.1 LRRK2 expression**

LRRK2 mRNA is highly expressed in the lungs, kidney, spleen and leucocytes; (Biskup et al., 2006; Li et al., 2007; Westerlund et al., 2008; White et al., 2007; Zimprich et al., 2004) however, its expression profile suggests that LRRK2 is unlikely to be an essential developmental protein (Biskup et al., 2007). In adult rodent brain, LRRK2 mRNA is somewhat restricted, with highest levels found in dopamine receptive areas but surprisingly low levels in the dopamine synthesizing areas (Biskup et al., 2006; Galter et al., 2006; Melrose et al., 2006; Simon-Sanchez et al., 2006; Taymans et al., 2006). LRRK2 protein levels do not entirely correlate with mRNA levels, suggesting transport following synthesis. LRRK2 protein is highly expressed in the spiny neurons in the striatum and in the dopamine neurons of the substantia nigra, (Biskup et al., 2006; Melrose et al., 2007) but robust expression is also found in many non-dopaminergic areas throughout the brain, for example the hippocampus and cerebellum (Biskup et al., 2006; Greggio et al., 2006; Higashi et al., 2007a; Higashi et al., 2007b; Melrose et al., 2007; Miklossy et al., 2006).

#### **2.3 Predicted function**

LRRK2 protein contains a GTPase domain as well as a kinase domain containing homologous sequence to tyrosine-like kinase (TLK), including mixed-lineage kinases (MLKs) and receptorinteracting kinases (RIPKs) (Mata et al., 2006). Given the size of the protein monomer (286kDa), its protein-protein interaction domains (ANK, LRR, WD40) and its propensity to dimerize, (Greggio et al., 2008) it is reasonable to postulate LRRK2 is part of a larger scaffolding complex. While *in silico* modeling suggests that LRRK2 mutations may have increased kinase activity and

The overall clinical profile in individuals with LRRK2 mutations is similar to that of typical late-onset PD (Aasly et al., 2005; Djaldetti et al., 2008; Healy et al., 2008). In agreement with observations in idiopathic PD, individuals with LRRK2-parkinsonism are generally responsive to levodopa treatment. While tremor, bradykinesia, and rigidity occurs in individuals with idiopathic PD, tremor is more frequently observed in individuals with

Disease duration, severity and response to treatment do not differ between G2019S carriers, regardless of zygosity (Ishihara et al., 2007, (Djaldetti et al., 2008) Individuals harboring LRRK2 G2019S present with similar non-motor features to idiopathic PD with the exception of a lower rate of cognitive impairment and hyposmia (Healy et al., 2008; Hulihan et al., 2008). Remarkably, there are aged G2019S carriers that escape disease (Carmine Belin et al., 2006; Kay et al., 2005). The LRRK2 G2019S mutation is primarily associated with transitional or brainstem Lewy body pathology, reminiscent of typical, late-onset idiopathic PD (Ross et al., 2006). LRRK2 mutation carriers presenting with tauopathy or ubiquitin-positive inclusions, with nigral neuronal loss and gliosis, have also been described (Wszolek et al., 2004; Dachsel et al., 2007; Rajput et al., 2006) Neuropathologic studies of affected individuals from other PARK8-linked kindreds, including Family A (Y1699C), Family D (R1441C), and the Sagamihara family (I2020T) have presented with pleomorphic pathology, including neuronal loss without co-existing pathology or with α-synuclein, ubiquitin-positive inclusions or tau pathology (Taylor et

LRRK2 mRNA is highly expressed in the lungs, kidney, spleen and leucocytes; (Biskup et al., 2006; Li et al., 2007; Westerlund et al., 2008; White et al., 2007; Zimprich et al., 2004) however, its expression profile suggests that LRRK2 is unlikely to be an essential developmental protein (Biskup et al., 2007). In adult rodent brain, LRRK2 mRNA is somewhat restricted, with highest levels found in dopamine receptive areas but surprisingly low levels in the dopamine synthesizing areas (Biskup et al., 2006; Galter et al., 2006; Melrose et al., 2006; Simon-Sanchez et al., 2006; Taymans et al., 2006). LRRK2 protein levels do not entirely correlate with mRNA levels, suggesting transport following synthesis. LRRK2 protein is highly expressed in the spiny neurons in the striatum and in the dopamine neurons of the substantia nigra, (Biskup et al., 2006; Melrose et al., 2007) but robust expression is also found in many non-dopaminergic areas throughout the brain, for example the hippocampus and cerebellum (Biskup et al., 2006; Greggio et al., 2006; Higashi et al., 2007a; Higashi et al., 2007b; Melrose et al., 2007;

LRRK2 protein contains a GTPase domain as well as a kinase domain containing homologous sequence to tyrosine-like kinase (TLK), including mixed-lineage kinases (MLKs) and receptorinteracting kinases (RIPKs) (Mata et al., 2006). Given the size of the protein monomer (286kDa), its protein-protein interaction domains (ANK, LRR, WD40) and its propensity to dimerize, (Greggio et al., 2008) it is reasonable to postulate LRRK2 is part of a larger scaffolding complex. While *in silico* modeling suggests that LRRK2 mutations may have increased kinase activity and

**2.2 Clinical and neuropathological features of LRRK2 parkinsonism** 

LRRK2 G2019S (Djaldetti et al., 2008; Healy et al., 2008; Hulihan et al., 2008).

al., 2006).

**2.2.1 LRRK2 expression** 

Miklossy et al., 2006).

**2.3 Predicted function** 

act through a dominant "gain-of-function", data on kinase activity across the different mutations has been controversial, with only the G2019S mutation consistently reported to enhance kinase activity compared to wild-type activity (Adams et al., 2005; Jaleel et al., 2007; Luzon-Toro et al., 2007; MacLeod et al., 2006; Smith et al., 2006; West et al., 2005).

LRRK2 has been characterized extensively in vitro. Although it is beyond the scope of this review to discuss these studies detail, several lines of evidence several lines of evidence point to a role in synaptic function (possibly by regulation of vesicle synthesis or transport and/or regulation of membranous structure) and as a regulator of neuronal outgrowth and guidance.
