Quinapyramine Suggestions Plus Myths

The decline in visual function is sensitive to the G2019S mutation as dopaminergic expression of other mutations within the LRRK2 gene, known to be pathogenic or to segregate with PD, shows no significant reduction in the fERG amplitude. Using other GAL4 drivers to express LRRK2-G2019S ubiquitously or in specific tissues of the eye, including the photoreceptors or lamina neurons, shows that the visual decline is specific for the expression of LRRK2-G2019S MS-275 molecular weight in DA neurons. Whilst externally the eyes of DA �� G2019S flies appear normal, the functional decline in vision of these flies is accompanied by anatomical neurodegeneration throughout the visual system. This includes disorganised retinas and frequent Quinapyramine vacuoles appearing in the second- and third-order visual neuropils (lamina and medulla) [49]. Antibody staining reveals an increase in autophagy and apoptosis around the microvilli of the photoreceptors of old DA �� G2019S flies. Electron micrographs show that the photoreceptor mitochondria of these flies become fragmented, swollen, and the cristae wider. DA neurons innervating the optic system were unperturbed in aged DA �� G2019S flies suggesting that the loss of visual function and degeneration of the photoreceptors precede any loss of dopaminergic innervation of the visual lobes. Increasing the demands on the visual system either through keeping flies in a pulsating light incubator or genetically through the introduction of the electrical-knock-in (EKI) transgene into the DA neurons to make them more active accelerates the GDC-0449 mw decline in visual function due to G2019S expression [49]. The accelerated degeneration of the visual system through increased neuronal activity led to the hypothesis that young DA �� G2019S flies could have amplified neuronal responses compared to wild-type flies. To test this hypothesis the steady-state visually evoked potential (SSVEP) method used in human visual electrophysiology was successfully translated to flies [15]. This technique is more sensitive than the widely used fERG because responses to many stimulus events are averaged together and out-of-band noise is eliminated from the analysis. One day after eclosion, DA �� G2019S flies had a dramatically increased contrast sensitivity compared to controls expressing the wild-type hLRRK2 or to those not expressing any transgene in their DA neurons [15]. The increased sensitivity of the DA �� G2019S flies is thought to originate in the photoreceptors and is inherited by the second-order lamina neurons. These results, taken with Hindle's observations, suggest that a period of hyperactivity of the visual system occurs in young DA �� G2019S flies. This starts an excitotoxic cascade (Figure 5), in which the flies soon start to suffer from an increased sensitivity to energy demand, followed by a cascade of degenerative events including apoptosis and autophagy.