Olsen, A. L. | Search bioRxiv

bioRxiv2024

Genetic screening and metabolomics identify glial adenosine metabolism as a therapeutic target in Parkinson's disease

Neuronal alpha-synucleinopathies, including Parkinson's disease (PD) and dementia with Lewy bodies (DLB), lack disease-modifying therapies. We developed a Drosophila model for identifying novel glial-based therapeutic targets for alpha-synucleinopathies. In this model, human alpha-synuclein is expressed in neurons and individual genes are independently knocked down in glia. We performed a forward genetic screen, knocking down the entire Drosophila kinome in glia in alpha-synuclein expressing flies. Among the top hits were five genes (Ak1, Ak6, Adk1, Adk2, and awd) involved in adenosine metabolism. Knockdown of each gene increased brain adenosine levels, improved locomotor dysfunction, reduced alpha-synuclein oligomer levels, and rescued neurodegeneration. We determined that the mechanism of neuroprotection requires adenosine signaling through the neuronal adenosine receptor (AdoR) in Drosophila. These experiments support glial adenosine as a novel therapeutic target in PD.

neuroscience↗

bioRxiv2022

Nicotine-mediated rescue of α-synuclein toxicity requires synaptic vesicle glycoprotein 2

BackgroundParkinsons disease (PD) is characterized by -synuclein aggregation and loss of dopamine (DA) neurons in the substantia nigra. Risk of PD arises due to a combination of genetic and environmental factors, which may interact, termed gene-environment (GxE) interactions. An inverse association between smoking and risk of PD is well-established, and a previous genome-wide GxE interaction study identified genetic variation in the synaptic-vesicle glycoprotein 2C (SV2C) locus as an important mediator of the degree to which smoking is inversely associated with PD. ObjectiveWe sought to determine the mechanism of the smoking-SV2C interaction in a Drosophila model of PD. MethodsFlies expressing human -synuclein in all neurons develop the hallmarks of PD, including motor dysfunction, loss of DA neurons, and formation of -synuclein inclusions. We assessed the effects of increasing doses of nicotine on these parameters of neurodegeneration, in the presence or absence of SV2 knockdown. Results-synuclein-expressing flies treated with nicotine had improvement in locomotion, DA neuron counts, and in -synuclein aggregation. However, in -synuclein-expressing flies in which Drosophila orthologs of SV2 were knocked down, nicotine failed to rescue neurodegeneration. ConclusionsThis work confirms a GxE interaction between nicotine and SV2, defines a role for this interaction in -synuclein proteostasis, and suggests that future clinical trials on nicotine should consider genetic variation in SV2C. Further, this provides proof of concept that our model can be used for mechanistic study of GxE, paving the way for investigation of additional GxE interactions or identification of novel GxE.

neuroscience↗