No Detectable Effect on Visual Responses Using Functional MRI in a Rodent Model of α-Synuclein Expression.

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.