Formic acid impairs α-synuclein seeding activity in human and mouse brains

Digraskar, S.; Dobbins, G. C.; Das, P.; Bash, R.; Songer, A.; Huh, J.; Scholz, K.; Khan, M.; Goldberg, M.; Gearing, M.; Volpicelli-Daley, L.; Chen, S.; Calvo, P. A.

doi:10.1101/2025.07.14.664807

bioRxiv · 10.1101/2025.07.14.664807

Formic acid impairs α-synuclein seeding activity in human and mouse brains

Digraskar, S.·Dobbins, G. C.·Das, P.·Bash, R.·Songer, A.·Huh, J.·Scholz, K.·Khan, M.·Goldberg, M.·Gearing, M.·Volpicelli-Daley, L.·Chen, S.·Calvo, P. A.

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Abstract

-Synuclein (-syn) is an abundant monomeric protein that can aggregate into fibrils and form neuropathological inclusions in the brains of patients with synucleinopathies. New evidence suggests that the mouse-human transmission barrier of -syn is lower than previously reported, emphasizing the need for improved biosafety procedures when working with -syn aggregates. Histopathology of -syn-infected brain represents a significant potential source of occupational exposure, and current methods for tissue fixation do not inactivate the ability of pathologic -syn to seed the conversion of endogenous, monomeric -syn into fibrils. In this study, we tested whether 96% formic acid treatment could reduce the seeding activity of -syn aggregates in paraformaldehyde-fixed brain samples from dementia with Lewy bodies (DLB) patients and -syn pre-formed fibrils (PFF)-injected mouse brains. Using real-time quaking-induced conversion (RT-QuIC), we found that formic acid treatment reduced -syn seeding dose (picograms of -syn seeds per ml of brain homogenate) in DLB and mouse brain by 6 and 8 logarithms, respectively. RT-QuIC reactions seeded with formic acid-treated brain homogenates showed significantly longer lag phase, and decreased total thioflavin T fluorescence compared to untreated samples, indicating that formic acid treatment impairs the ability of pathological -syn to seed monomeric -syn. Importantly, the -syn pathologic features and the immunostaining quality were preserved in formic acid-treated tissues. Our results demonstrate that formic acid treatment is a quick and efficient procedure for reducing -syn seeding activity in fixed brain samples, thereby lowering the risk of accidental exposure in laboratories without compromising the quality of histopathological analysis. SummaryFormic acid treatment drastically reduces -synuclein seeding activity in fixed human and mouse brain samples while preserving histopathological quality.

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Digraskar, S., Dobbins, G. C., Das, P., Bash, R., Songer, A., Huh, J., Scholz, K., Khan, M., Goldberg, M., Gearing, M., Volpicelli-Daley, L., Chen, S., Calvo, P. A.. 2025-07-18. Formic acid impairs α-synuclein seeding activity in human and mouse brains. https://doi.org/10.1101/2025.07.14.664807

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