Abstract
Loss of the sense of smell is among the first signs of natural aging and neurodegenerative diseases such as Alzheimer's and Parkinson's. Cellular and molecular mechanisms promoting this smell loss are not understood. Here, we show that Drosophila melanogaster also loses olfaction before vision with age. Within the olfactory circuit, cholinergic projection neurons show a reduced odor response accompanied by a defect in axonal integrity and reduction in synaptic marker proteins. Using behavioral functional screening, we pinpoint that expression of the mitochondrial reactive oxygen scavenger SOD2 in cholinergic projection neurons is necessary and sufficient to prevent smell degeneration in aging flies. Together, our data suggest that oxidative stress induced axonal degeneration in a single class of neurons drives the functional decline of an entire neural network and the behavior it controls. Given the important role of the cholinergic system in neurodegeneration, the fly olfactory system could be a useful model for the identification of drug targets.
Highlights
Such a reporter construct for the localization of Acetylcholine receptors expressed in PNs (GH146 > Da7-GFP) revealed a moderate, but significant signal reduction of this postsynaptic marker at PN postsynaptic sites in the antennal lobe (AL) indicating an aging-related change at the post-synapse (Figure 3G,I)
We pinpoint that expression of the mitochondrial reactive oxygen scavenger SOD2 in cholinergic projection neurons is necessary and sufficient to prevent smell degeneration in aging flies
Our data suggest that oxidative stress induced axonal degeneration in a single class of neurons drives the functional decline of an entire neural network and the behavior it controls
Summary
Such a reporter construct for the localization of Acetylcholine receptors expressed in PNs (GH146 > Da7-GFP) revealed a moderate, but significant signal reduction of this postsynaptic marker at PN postsynaptic sites in the AL indicating an aging-related change at the post-synapse (Figure 3G,I). Given the dramatic reduction of responsive presynaptic PN boutons in the MB calyx and the reduced response in the AL observed by GCaMP imaging (see Figure 2), we employed antibody staining against the enzyme ChAT (Choline Acetyltransferase) required for the production of Acetylcholine at synapses of cholinergic neurons such as the PNs. Quantification of these stained brains revealed a significant reduction in ChAT positive puncta in the AL and at the level of the MB
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