Parkin Protects against LRRK2 G2019S Mutant-Induced Dopaminergic Neurodegeneration in Drosophila

Abstract

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are currently recognized as the most common genetic cause of parkinsonism. Among the large number of LRRK2 mutations identified to date, the G2019S variant is the most common. In Asia, however, another LRRK2 variant, G2385R, appears to occur more frequently. To better understand the contribution of different LRRK2 variants toward disease pathogenesis, we generated transgenic Drosophila over-expressing various human LRRK2 alleles, including wild type, G2019S, Y1699C, and G2385R LRRK2. We found that transgenic flies harboring G2019S, Y1699C, or G2385R LRRK2 variant, but not the wild-type protein, exhibit late-onset loss of dopaminergic (DA) neurons in selected clusters that is accompanied by locomotion deficits. Furthermore, LRRK2 mutant flies also display reduced lifespan and increased sensitivity to rotenone, a mitochondrial complex I inhibitor. Importantly, coexpression of human parkin in LRRK2 G2019S-expressing flies provides significant protection against DA neurodegeneration that occurs with age or in response to rotenone. Together, our results suggest a potential link between LRRK2, parkin, and mitochondria in the pathogenesis of LRRK2-related parkinsonism.

Biochemical and molecular features of LRRK2 and its pathophysiological roles in Parkinson's disease

“…Another recent study revealed that over-expression of LRRK2 accelerates the progression of neuropathological phenotypes in transgenic mice with the A53T α-synuclein mutation (85). In addition, Parkin alleviated dopaminergic neuronal loss mediated by over-expression of LRRK2 G2019S mutants (86). Combined together, these reports suggest functional linkages among the various FPD genes.…”

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

“…Importantly, this effect was diminished by pharmacological inhibition of kinase activity of G2019S mutant or by overexpression of parkin, a protein implicated in autosomalrecessive Parkinsonism [116,117]. It was also suggested that DA neuron loss in Drosophila triggered by overexpression of G2019S hLRRK2 is caused by an increase in bulk protein synthesis and be prevented by overexpression of the phosphodeficient T136A ribosomal protein s15 [118].…”

“…In Drosophila, a dLRRK Y1383C mutant (analogous to human Y1699C) caused prominent vesicular aggregation of the protein and DA neuron loss [75]. Transgenic overexpression of human Y1699C or G2385R LRRK2 in Drosophila is also associated with DA neuron loss accompanied by locomotor deficits [117,122].…”

Paraquat, Between Apoptosis and Autophagy

“…There have also been studies that relate LRRK2 and apoptosis (Ho et al, 2009). Previous studies have shown a relationship between LRRK2 and other PD-related proteins, such as parkin (Ng et al, 2009;, PINK-1 and DJ-1 (Venderova et al, 2009) or α-synuclein (X. Lin et al, 2009).…”