Abstract
Parkinson’s disease (PD) is a progressive neurodegenerative disease that is typically diagnosed late in its progression. There is a need for biomarkers suitable for monitoring the disease progression at earlier stages to guide the development of novel neuroprotective therapies. One potential biomarker, α-synuclein, has been found in both the familial cases of PD, as well as the sporadic cases and is considered a key feature of PD. α-synuclein is naturally present in the retina, and it has been suggested that early symptoms of the visual system may be used as a biomarker for PD.
Here, we use a viral vector to induce a unilateral expression of human wildtype α-synuclein in rats as a mechanistic model of protein aggregation in PD. We employed functional magnetic resonance imaging (fMRI) to investigate whether adeno-associated virus (AAV) mediated expression of human wildtype α-synuclein alter functional activity in the visual system. 16 rats were injected with either AAV-α-synuclein (n=7) or AAV-null (n=9) in the substantia nigra pars compacta of the left hemisphere. The expression of α-synuclein was validated by a motor assay and post-mortem immunohistochemistry. Five months after the introduction of the AAV-vector, fMRI showed robust blood oxygen level dependent (BOLD) responses to light stimulation in the visual systems of both control and AAV-α-synuclein animals. However, our results demonstrate that the expression of AAV-α-synuclein does not affect functional activation of the visual system. This negative finding suggests that fMRI-based read-outs of visual responses may not be a sensitive biomarker for PD.
Significance statement
We injected an adeno-associated virus (AAV) vector in rats to induce unilateral expression of human wildtype α-synuclein in the substantia nigra, and in the ipsilateral striatum and superior colliculus (SC). This did not affect functional activation of SC as probed with functional MRI. This negative finding discourages the use of functional brain mapping of visually evoked activity as an indicator of regional expression of human α-synuclein.
Footnotes
Hartwig R. Siebner has received honoraria as speaker from Sanofi Genzyme, Denmark and Novartis, Denmark, as consultant from Lundbeck AS, Denmark and Sanofi Genzyme, Denmark, and as senior editor (NeuroImage) and Editor-in-Chief (Neurimage-Clinical) from Elsevier Publishers, Amsterdam, The Netherlands. He has received royalties as book editor from Springer Publishers, Stuttgart, Germany, and Gyldendal, Copenhagen, Denmark.
This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 641805. HRS holds a 5-year professorship in precision medicine at the Faculty of Health Sciences and Medicine, University of Copenhagen which is sponsored by the Lundbeck Foundation (Grant Nr. R186-2015-2138).
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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