Limits...
Abnormal visual gain control in a Parkinson's disease model.

Afsari F, Christensen KV, Smith GP, Hentzer M, Nippe OM, Elliott CJ, Wade AR - Hum. Mol. Genet. (2014)

Bottom Line: Biochemical and cellular assays suggested that BMPPB-32 would be a more specific kinase inhibitor than LRRK2-IN-1.We confirmed this in vivo, finding that dLRRK(-) flies show large off-target effects with LRRK2-IN-1 but not BMPPB-32.Our data link the increased Kinase activity of the G2019S-LRRK2 mutation to neuronal dysfunction and demonstrate the power of the Drosophila visual system in assaying the neurological effects of genetic diseases and therapies.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology and.

Show MeSH

Related in: MedlinePlus

Modelling of the contrast response functions confirms the abnormality of the visual response in 1-day-old TH>G2019S flies. Fitting the hyperbolic ratio function for TH>G2019S, TH>hLRRK2 and TH/+ for 1F1 (A) and 2F1 (B) provides estimates of c50 (C) and Rmax (D). These show that expression of LRRK2-G2019S in the dopaminergic neurons shifts the 1F1 contrast response function to the left with both the masked and unmasked stimulation. However, the unmasked 2F1 contrast response function shows a leftward shift but masking affects Rmax. Original data plotted in Figure 4, while statistical tests are provided in Figure 8 and Table 1.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4119403&req=5

DDU159F5: Modelling of the contrast response functions confirms the abnormality of the visual response in 1-day-old TH>G2019S flies. Fitting the hyperbolic ratio function for TH>G2019S, TH>hLRRK2 and TH/+ for 1F1 (A) and 2F1 (B) provides estimates of c50 (C) and Rmax (D). These show that expression of LRRK2-G2019S in the dopaminergic neurons shifts the 1F1 contrast response function to the left with both the masked and unmasked stimulation. However, the unmasked 2F1 contrast response function shows a leftward shift but masking affects Rmax. Original data plotted in Figure 4, while statistical tests are provided in Figure 8 and Table 1.

Mentions: We have shown that the SSVEP technique generates CRFs that strongly resemble those of humans, that the 1F1 component represents photoreceptor signalling and that the 2F1 and 2F1+2F2 represent separate stages of the neuronal response. Our hypothesis is that the degeneration seen in old flies expressing LRRK2-G2019S was due to hyperactivity at an early age. Therefore, we next ask if the SSVEP technique is powerful enough to reveal small changes due to dopaminergic expression of the PD-related mutation G2019S in the youngest flies, when they are 1 day old. We used the tyrosine hydoxylase (TH) GAL4 (44) to drive expression of either normal human hLRRK2 or hLRRK2-G2019S and compared these with a cross between the GAL4 and wild-type flies (TH/+) that do not express a human transgene. Data are displayed in three figures: the raw data in Figure 4, the fitted curves in Figure 5 and the phase data in Figure 6. Statistical analysis is given in Figure 8 and Table 1.Table 1.


Abnormal visual gain control in a Parkinson's disease model.

Afsari F, Christensen KV, Smith GP, Hentzer M, Nippe OM, Elliott CJ, Wade AR - Hum. Mol. Genet. (2014)

Modelling of the contrast response functions confirms the abnormality of the visual response in 1-day-old TH>G2019S flies. Fitting the hyperbolic ratio function for TH>G2019S, TH>hLRRK2 and TH/+ for 1F1 (A) and 2F1 (B) provides estimates of c50 (C) and Rmax (D). These show that expression of LRRK2-G2019S in the dopaminergic neurons shifts the 1F1 contrast response function to the left with both the masked and unmasked stimulation. However, the unmasked 2F1 contrast response function shows a leftward shift but masking affects Rmax. Original data plotted in Figure 4, while statistical tests are provided in Figure 8 and Table 1.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4119403&req=5

DDU159F5: Modelling of the contrast response functions confirms the abnormality of the visual response in 1-day-old TH>G2019S flies. Fitting the hyperbolic ratio function for TH>G2019S, TH>hLRRK2 and TH/+ for 1F1 (A) and 2F1 (B) provides estimates of c50 (C) and Rmax (D). These show that expression of LRRK2-G2019S in the dopaminergic neurons shifts the 1F1 contrast response function to the left with both the masked and unmasked stimulation. However, the unmasked 2F1 contrast response function shows a leftward shift but masking affects Rmax. Original data plotted in Figure 4, while statistical tests are provided in Figure 8 and Table 1.
Mentions: We have shown that the SSVEP technique generates CRFs that strongly resemble those of humans, that the 1F1 component represents photoreceptor signalling and that the 2F1 and 2F1+2F2 represent separate stages of the neuronal response. Our hypothesis is that the degeneration seen in old flies expressing LRRK2-G2019S was due to hyperactivity at an early age. Therefore, we next ask if the SSVEP technique is powerful enough to reveal small changes due to dopaminergic expression of the PD-related mutation G2019S in the youngest flies, when they are 1 day old. We used the tyrosine hydoxylase (TH) GAL4 (44) to drive expression of either normal human hLRRK2 or hLRRK2-G2019S and compared these with a cross between the GAL4 and wild-type flies (TH/+) that do not express a human transgene. Data are displayed in three figures: the raw data in Figure 4, the fitted curves in Figure 5 and the phase data in Figure 6. Statistical analysis is given in Figure 8 and Table 1.Table 1.

Bottom Line: Biochemical and cellular assays suggested that BMPPB-32 would be a more specific kinase inhibitor than LRRK2-IN-1.We confirmed this in vivo, finding that dLRRK(-) flies show large off-target effects with LRRK2-IN-1 but not BMPPB-32.Our data link the increased Kinase activity of the G2019S-LRRK2 mutation to neuronal dysfunction and demonstrate the power of the Drosophila visual system in assaying the neurological effects of genetic diseases and therapies.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology and.

Show MeSH
Related in: MedlinePlus