Flies and mice get Parkinson's the same way
Drosophila gets Parkinson's disease (PD): the same genetic changes that cause PD in man, including loss of function in parkin or DJ1, and gain of function or too much alpha synuclein or LRRK2, also cause a PD-like disease in flies. Remarkably, neurons producing the same neurotransmitter - dopamine - are primarily affected in both man and flies, demonstrating the extensive conservation of specific neuronal molecular biology. More of this in later blogs!
But how does the fly system compare with the gold standard for PD modelling and drug testing, the mouse? Two recent publications by Smith et al., 2010 and Hernández-Vargas et al. 2011 show that two key PD proteins - alpha synuclein and synphilin 1 - act and interact in exactly the same way in the dopamine neurons of flies and mice.
Certain mutations in the human alpha synuclein gene (A53T, A30P, E46K) cause early onset PD. Alpha synuclein is a major constituent of Lewy Bodies (LB), a characteristic pathological feature of PD - and another major LB constituent is synphilin 1, a synaptic protein that interacts with alpha synuclein. Many studies show that overexpression of human wild type or familial PD mutant forms of alpha synuclein causes neurodegeneration in both mice and Drosophila. The role of synphilin1 has been less clear, although a point mutation (R621C) has been found in some sporadic PD cases (Marx et al., 2003)
Smith et al. studied transgenic mice expressing either A53T alpha synuclein alone or A53T alpha synuclein plus synphilin 1, both from the mouse prion gene promoter. They showed that co-expression of synphilin 1 with alpha synuclein really reduced the severity of the neurodegenerative disease phenotype due to alpha synuclein toxicity: brainstem neuronal loss was reduced by 50% and the astroglial reaction by 43%. These data indicate that synphilin 1 has a regulatory role in preventing alpha synuclein toxicity.
What happens in flies? Hernández-Vargas et al. show that neurodegeneration caused in Drosophila by alpha synuclein wild type, A53T or A30P is significantly reduced by co-expression of synphilin 1. This was studied both by general neuronal expression and by specific expression in dopaminergic neurons. As would be expected, fly motility was rescued and survival was enhanced by synphilin 1 co-expression.
These data suggest that neurons need alpha synuclein for optimal function, and a health and safety system developed early in evolution, involving synphilin1. The mechanism of this safety valve is clearly important for PD therapy, and both sets of authors have suggestions about this.
As Hernández-Vargas et al. remark on page 398, "This work showcases Drosophila as an excellent model for neurodegenerative disease..."
Brainwave-Discovery Ltd. is expressing both alpha synuclein and synphilin 1 in Drosophila synapses. We can help you find out the in vivo effects of your compounds on interactions of alpha synuclein with its partners, within normal or various Parkinson's disease backgrounds. We also link in to a Europe-wide synaptic analysis network, SynSys). For more information check out our website or contact firstname.lastname@example.org
- Hernández-Vargas R. et al.. 2011, Genesis 49, 392-402
- Marx, FP et al., 2003 Hum. Molec. Genet. 12, 1223-1231
- Smith W.W. et al. 2010, Hum. Molec. Genet. 19, 2087-2098