Parkinson's disease (PD) is a common and currently incurable neurodegenerative movement disorder affecting approximately 1–2% of the population over 65 years of age. Clinically, it is characterized by age-dependent resting tremor, muscular rigidity, and akinesia. Neuropathologically, selective loss of dopaminergic (DA) neurons in the substantia nigra compacta region and Lewy body formation in the remaining neurons are two hallmarks of PD patient brains [1
The molecular mechanism of PD-specific neuropathological changes and parkinsonism motor deficits are largely unknown. Nevertheless, significant progress on molecular genetics of PD has been made during the last several years by studying familial PD cases. Mutations in at least 7 genes have been implicated in various forms of familial PD cases. These genes include α-synuclein, uchL1, LRRK2, parkin, PINK1, DJ-1, and ATP13A2 [2
was recently identified as a novel gene responsible for an autosomal dominant form of PD, suggesting a toxic gain of function of LRRK2 in affected cases [3
]. So far, at least 20 LRRK2
mutations have been identified from PD patients, accounting for ~7% familial form of PD cases and for a significant portion of sporadic PD cases [11
]. Unlike other PD-associated genes, which normally are correlated with early-onset or pathologically atypical forms of PD, LRRK2
is associated with late-onset and clinically idiopathic PD [3
]. Thus, dysfunction of LRRK2 may impair a common pathway involving in pathogenesis of both familial and sporadic PD cases.
LRRK2 is a large protein (2527 amino acids) consisting of several independent domains, including a leucine-rich repeat domain, a Roc GTPase domain followed by its associated C terminal of Roc (Rac) domain, a protein kinase domain of the MAPKKK family, and a C-terminal WD40 domain [13
], suggesting a complexity of its cellular function and regulation. Recent studies suggest that LRRK2 can self-phosphorylate in vitro
. Moreover, the kinase activity of LRRK2 seems to be tightly regulated by its GTPase activity [15
]. PD related mutations results in increased kinase activity of LRRK2 [16
]. Thus, inactivation of LRRK2 kinase activity constitutes a potential strategy for PD treatment. A critical point for this treatment strategy is whether inhibition of LRRK2 physiological activity will affect the normal development process or induce severe pathological side effects.
In the present study, we investigated roles of LRRK2 in development and neuronal survival using Drosophila as a model system. Our results suggest that LRRK2 kinase activity is not required for development, survival of DA neurons, and protection of PD-related stress of Drosophila.