Abstract
Mutations within Leucine-rich repeat kinase 2 (LRRK2) are associated with late-onset Parkinson’s disease. The physiological function of LRRK2 and molecular mechanism underlying the pathogenic role of LRRK2 mutations remain uncertain. Here, we investigated the role of LRRK2 in intracellular signal transduction. We find that deficiency of Lrrk2 in rodents affects insulin-dependent translocation of glucose transporter type 4 (GLUT4). This deficit is restored during aging by prolonged insulin-dependent activation of protein kinase B (PKB, Akt) and Akt substrate of 160 kDa (AS160), and is compensated by elevated basal expression of GLUT4 on the cell surface. Furthermore, we find a crucial role of Rab10 phosphorylation by LRRK2 for efficient insulin signal transduction. Translating our findings into human cell lines, we find comparable molecular alterations in fibroblasts from Parkinson’s patients with the known pathogenic G2019S LRRK2 mutation. Our results highlight the role of LRRK2 in insulin-dependent signalling with potential therapeutic implications.
Highlights
After stimulation with insulin the rapid intracellular translocation of glucose transporter type 4 (GLUT4) to the cell surface fails in Lrrk[2] deficient cells from 6 months old animals. This malfunction is accompanied by slight elevation of protein kinase B (PKB, Akt) phosphorylation. We find that this defect is restored during aging by prolonged insulin-dependent activation of Akt and Akt substrate of 160 kDa (AS160/ TBC1D4), and is compensated by elevated basal levels of GLUT4 on the plasma membrane
We found a significant (p = 0.0488) up-regulation in phosphorylation at Thr[642] before stimulation in fibroblasts from 22 months old Lrrk[2] deficient rats (Fig. 5c), which is in agreement with our data for increased GLUT4 immunostaining at time point 0 (Fig. 4d)
Within this study we investigated the possible role of the Parkinson’s disease-linked Leucine-rich repeat kinase 2 (LRRK2) in intracellular signalling and showed that LRRK2 plays a crucial role in insulin-dependent signal transduction
Summary
We find that deficiency of Lrrk[2] affects selectively insulin-dependent intracellular signalling. After stimulation with insulin the rapid intracellular translocation of glucose transporter type 4 (GLUT4) to the cell surface fails in Lrrk[2] deficient cells from 6 months old animals. This malfunction is accompanied by slight elevation of protein kinase B (PKB, Akt) phosphorylation. We find comparable molecular dys-regulations in fibroblasts from Parkinson’s patients with G2019S mutated LRRK2. Our data demonstrates that the Parkinson’s disease-linked LRRK2 plays a crucial role in insulin-driven translocation and/or fusion of GLUT4-vesicles to the plasma membrane through the phosphorylation of Rab[10]
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