Human vision can be affected by diseases of the central nervous system—for example, epilepsy, Parkinson’s disease and dementia. In some cases, these diseases can be traced to mutations in a single gene and, remarkably, mutations of the counterparts of these genes in fruit flies cause conditions that resemble the human disease. This project seeks to understand the effect that single gene mutations have on neural function in both humans and flies. The data acquired will help in diagnosing, understanding, modelling and treating human neurological disease.
Our goal was to understand how visual signaling is affected in flies carrying mutations in disease-related genes.
We constructed a system, based on the human Steady State Visual Evoked Potential (SSVEP) technique, to obtain steady-state measurements of visual function in flies (objective 1). We found that flies generate robust and consistent signals, with a much better signal/noise ration than the mammalian data. Wild-type flies had Contrast vs Response Functions (CRFs) which strongly resembled those recorded in mammalian and human SSVEP data. This indicates a high degree of functional homology to go with the anatomical homology first described by Ramon y Cajal 100 years ago. This means that any studies of lesions in Drosophila caused by the expression of disease related genes are likely to have high relevance to the human condition.
To show that the SSVEP analysis was accurate (objective 2), we tested flies carrying histamine receptor mutations, which have known lesions in the visual system. As we expected, the responses were quite different in the histamine knockouts : they lacked the frequency components that we hypothesized were due to neuronal signalling. This verification of the origins of our SSVEP signals makes it straightforward to apply the technique to flies carrying genetic models of human disease.
Epilepsy: Understanding visual stimuli in epilepsy is important as flash photography, or rapid scene changes on TV or video games can induce epileptic fits in patients. A small number of patients have inherited mutations in the K+/Cl- transporter gene hKCC2. We found that flies with mutations in the homologous kcc that have visual deficits including sudden visual stimuli induced paroxysmal discharges and much stronger spontaneous rhythmic activity than wild-type flies.
Parkinson’s disease: A small proportion of Parkinson’s disease (PD) is inherited. The most common cause is a mutation, G2019S in the hLRRK2 gene. This mutation may also play a role in many sporadic PD. We examined flies expressing mutated hLRRK2-G2019S, and found that steady-state measurements could identify lesions in the visual system long before those seen in “traditional” electroretinograms, (and before any movement defects were observed). Flies carrying extra copies of the normal human hLRRK2 gene were unaffected. The SSVEP signals were reverted to normal by three novel LRRK2 inhibitors. This data provides the first in vivo model of LRRK2 which is amenable to fast throughput screening of LRRK2 inhibitors. The development of the LRRK2 inhibitor drugs is of tremendous importance as the current mainstay of PD treatment, L-DOPA, has a time-limited effectiveness.
These data emphasize the strong homology between flies and humans in visual processing and their potential role in diagnosing, understanding and developing therapies for neuronal disease
Any substantial new collaborations that have been set-up as a result of funding.
Commercial exploitation: We received supplies of a LRRK inhibitor for first in vivo testing from Lundbeck. We visited Lundbeck in Spring 2013, and presented the work. Lundbeck are facilitating one of us (ARW) to visit Tunisia with a view to screening a cohort of PD patients that frequently (up to 30%) carry the G2019S mutation. We are finalising negotiations with Pfizer (who have agreed to supply other LRRK2 inhibitors) and have discussed possible collaboration with Brainwave-Discovery. We have also developed a collaboration with Zhenyu Yue (Mount Sinai School of Medicine).
How many postdocs were employed on the project and for how long. Please also indicate if any of them subsequently moved onto new contracts of a year or more with the PI or any of the co-PIs.
1 postdoc, employed for 12 months, still working with CJHE and ARW.
Funder: NC3Rs: PI: A.R. Wade, Title: Drosophila: A direct model of human epilepsy, Amount: £420,000 (FEC), Start date: Sept 1 2013. End data: Aug 31 2016, pFACT number: 14071 [unfunded]
Funder: Parkinson’s UK : PI: cjh electroretinogram, Title: Optimising an in vivo assay for inhibitors of LRRK2, Amount: £201,827 (Charity), Start date: Sept 1 2013. End data: Aug 31 2016, pFACT number: 14664 [unfunded]
Funder: The Wellcome Trust, PI ARW. Co PIs CJHE, MEP, SLS. Amount 117,000, Title: From bench to bedside: the role of LRRK2
Funder: Parkinson’s UK PI: CJHE £88,213 Role of dopamine and LRRK2 mutants in the decline of vision (Phd studentship)
Funder. The Wellcome Trust PI: R West [value not yet known] Genetic dissection of visual Parkinson’s disease phenotype
Funder: The Physiological Society PI CJHE [Outreach grant, £750] Vision in locusts
Farinaz Afsari1, Kenneth V. Christensen2, Garrick Paul Smith2, Morten Hentzer2, Christopher J. H. Elliott1, Alex R. Wade3*
1) Department of Biology, University of York, YO1 5DD, UK
2) Neuroscience Drug Discovery DK, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark
3) Department of Psychology, University of York, YO1 5DD, UK
Abnormal visual gain control in a Parkinson's Disease model (Under revision with Human Molecular genetics)
CJHE present data to local PD groups, and his work was selected for the Parkinson's' UK Pathfinder project, a financial appeal to the 500 top donors to Parkinson's UK