Role of Parkinson's disease genes in flies
Research outline
Model organisms, like flies, provide a rapid experimental system to
study the causes of Parkinson's disease. I collaborate with Sean
Sweeney, Alex Wade Gareth
Evans, Sangeeta
Chawla, Gonzalo Blanco and Will Brackenbury to form the York Neuroscience
Group, where
we
focus on neurotransmission in model systems.
My key question is how cellular defects (e.g.
faulty mitochondria) lead to physiological and behavioural
abnormalities - In Parkinson's Disease (PD), why do some neurons die, while others function
normally?
LRRK2
- We find that flies expressing the G2019S mutation (but not other
mutations in LRRK2) have accelerated loss of vision, and this is most
pronounced when the G2019S transgene is expressed in just the
dopaminergic neurons. Our data
- suggests a hypothesis, that differences between older reports
on visual defects in PD patients may arise from genetic differences
between the patients.
- shows that expressing the G2019S mutation in the dopaminergic
neuron leads to loss of function in different kinds of neuron - e.g. the
photoreceptors, which have nothing to do with dopamine.
- shows that increasing the activity of the visual system
accelerates the decline in the G2019S mutation
- Details
here.
This work is being pursued in collaboration with Alex Wade
and Naz Afsari on a Wellcome Trust grant, and by Rebecca Furmston and
Stavroula Petridi on White Rose and Parkinson's UK studentships.
parkin
Other work with flies...
Snails
My earlier work
at York was with the pond snail Lymnaea stagnalis.
This
is what the snails look like. In particular, I'm interested
in how
their nervous system controls
feeding
behaviour, because this is a really robust model system. A major part
of my time was taken up with using laser ablation and pharmacological
tools to
analyze the neural circuits. My key finding was that octopamine is very
important in the feeding system,
as it modulates the behaviour at multiple levels, making it more
efficient and longer
lasting.
Computer Software
I (intermittently) write computer software to aid in the modeling of
nervous
systems: read (&download) all about the Hodgkin-Huxley
simulation and Connor
(with IA) models.
Recent publications include
72.
Middleton, C.A., Nongthomba, U., Parry, K., Sweeney, S.T., Sparrow,
J.C. Elliott, C.J.H. (2006) Neuromuscular organization and aminergic
modulation of contractions in the Drosophila ovary BMC Biology
4:17 Full
text (free access)
73.
Large, C.J., Smith, T., Foulds, G., Currey, J.D. and Elliott, C.J.H.
(2006) Leaf mechanical properties modulate feeding movements and
ingestive success of the pond snail, Lymnaea stagnalis. Invert.
Neurosci. 6: 133-140 Abstract
74.
Ormshaw, J. C., C. J. H. Elliott (2006) Octopamine boosts
snail
locomotion: behavioural and cellular analysis. Invert. Neurosci 6:
215-220. Abstract
75.
Vehovszky, A., Szabo, H., Hiripi, L., Elliott, C.J.H. and Hernadi, L.
(2007) Behavioural and neural deficits induced by rotenone in the pond
snail Lymnaea stagnalis. A possible model for Parkinson’s disease
in an invertebrate. Eur J. Neurosci
25:2123–2130 Abstract
76.
Elliott, C.J.H. Brunger, H., Stark, M. and Sparrow, J.C. (2007) Direct
measurement of the performance of the Drosophila jump muscle in whole
flies. Fly 1:68 - 74 Abstract
78.
Harvey, J., Brunger, H., Middleton, C.A., Hill, J.A., Sevdali, M.,.
Sweeney, S.T., Sparrow, J.C. and Elliott, C. J. H. (2008) Neuromuscular
control of a single twitch muscle in wild type and mutant Drosophila,
measured with an ergometer. Invertebrate neuroscience 8:63-70 Abstract
Author
manuscript
79.
Norville,
K., Sweeney, S.T. and Elliott, C.J.H (2010)
Post mating change in physiology of male Drosophila mediated by 5-HT.
J.
Neurogentics 24: 27–32 Abstract
Author
manuscript
80. Elliott, C. J. H. and Sparrow, J.C. (2012) In vivo measurement
of muscle output in intact Drosophila. Methods 56:78-86 Abstract
Author
manuscript Supplementary
movie
81.
Vincent,
A., Briggs, L., Chatwin, G.F.J., Emery, E., Tomlins, R., Oswald, M., Middleton,
C.A.,
Evans, G.J.O., Sweeney,
S.T., Sparrow,
J.C. and Elliott, C.J.H. (2012) parkin
induced defects in neurophysiology and locomotion are generated by
metabolic
dysfunction and not oxidative stress. Hum. Mol. Gen. 21: 1760-1769, Abstract & Free Full text
82. Katzemich A R, Kreisk\F6ther N, Alexandrovich A,
Elliott, C J H, Sch\F6ck F, Leonard K R, Sparrow J C, and Bullard,
B. (2012) The function of the M-line protein, obscurin, in
controlling the symmetry of the sarcomere in Drosophila flight muscle.
J cell Sci. 125, 3367-3379 Abstract
83. Diaper D C, Yoshitsugu A, Sutcliffe B, Humphrey,
D M, Elliott, C J H, Stepto A, Ludlow Z N, Vanden Broeck L, Callaerts
P, Dermaut B, Al-Chalabi A, Shaw C E, Robinson IM and Frank Hirth
(2013) Loss and gain of Drosophila TDP-43 impair synaptic efficacy and
motor control leading to age-related neurodegeneration by loss. Hum.
Mol. Genetics 22: 1539-1557 Abstract and free Full text
84. Hindle, S., Afsari, F, Stark, M, Middleton, C.A.,
Evans, G J O, Sweeney, S T, and Elliott, C J H (2013) Dopaminergic
expression of the Parkinsonian gene LRRK2-G2019S leads to
non-autonomous visual neurodegeneration, accelerated by increased
neural demands for energy. Hum. Mol. Genetics 22: 2129-2140 Abstract and free Full text
85. Hindle, S. & Elliot, C.J.H. (2013) Spread of neuronal
degeneration in a dopaminergic, Lrrk2-G2019S model of
Parkinson's disease. Autophagy. 9: 936-938. Abstract
and Free Full text
86. Afsari, F., Christensen, K.V., Smith, G.P.,
Hentzer, M., Nippe, O.M., Elliott, C.J.H. and Wade, A.R. (2014)
Abnormal visual gain control in a Parkinson's Disease model Hum. Mol. Genetics 23: 4465-4478 Abstract and free full text
87. Fogg, P.C.M., O'Neill, J.S., Dobrzycki, T., Calvert, S., Lord, E.C., McIntosh, R.L.L., Elliott, C.J.H., Sweeney, S.T., Hastings, M.H. and Chawla, S. (2014) Class IIa histone deacetylases are conserved regulators of circadian function. J. Biol. Chem. 289: 34341-34348 Abstract and Free full text
88. Wade, A.R. and Elliott, C.J.H. (2014) Could the detection of visual disturbances associated with Parkinsons disease genes in flies lead to new treatments for the disease? Neurodegenerative Disease Management 4:291-293 Abstract
and Free Full text
89. West, R. J.H. Furmston, R., Williams, C.A.C & Elliott, C.J.H. (2015) Neurophysiology of Drosophila models of Parkinson's Disease Parkinson's disease 2015:381281 Abstract and free full text
90. Orfanos, Z., Leonard, K., Elliott, C.J.H., Katzemich, A., Bullard, B., & Sparrow, J.C (2015) Sallimus and the dynamics of sarcomere assembly in Drosophila flight muscles.
J mol biol 427: 215-218 Abstract and free full text
91. Smith, S.L., Lones, M., Bedder, M. Alty, J.A., Cosgrove, J., Maguire, R.J. & Pownall, M.E., Ivanoiu, D., Lyle, C., Cording, A. &
Elliott, C.J.H., (2015) Computational models for understanding the diagnosis and treatment of Parkinsons disease. IET Systems Biology
Abstract
Full Text (Pubmed)
92. Mortiboys, H., Furmston, R., Bronstad, G., Aasly, J., Elliott, C.J.H., & Bandmann, O. (2015) UDCA exerts beneficial effect on mitochondrial dysfunction in LRRK2 G2019S carriers
and in vivo.
Neurology Abstract
Free full text
93.West, R. J.H., Elliott, C.J.H. & Wade, A.R. (2015) Classification of Parkinson’s Disease Genotypes in Drosophila Using Spatiotemporal Profiling of Vision. Nature Sci Rep 5:16933
Abstract and free full text
94. Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A, ...
Elliott, C.J.H. ... Zorzano A, & Zughaier SM. (2016) Guidelines for the use
and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 12:1-222. Abstract & Free Full text
Chris Elliott
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