Pathological α-Synuclein Perturbs Nuclear Integrity

Millett, M.; Comite, A.; Castosa, E. M.; Heuberger, A.; Wagner, P.; Gallardo, I.; Reinhardt, J.; Chambers, N.; Hall, D.; Miller, E.; Nabert, D.; Balsamo, B.; Prokop, S.; Moehle, M.

doi:10.1101/2025.03.04.641384

bioRxiv · 10.1101/2025.03.04.641384

Pathological α-Synuclein Perturbs Nuclear Integrity

Millett, M.·Comite, A.·Castosa, E. M.·Heuberger, A.·Wagner, P.·Gallardo, I.·Reinhardt, J.·Chambers, N.·Hall, D.·Miller, E.·Nabert, D.·Balsamo, B.·Prokop, S.·Moehle, M.

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Abstract

Pathological aggregates of -synuclein are a hallmark of a group of neurodegenerative disorders collectively termed synucleinopathies. The physiological function of -synuclein, and the detrimental effects of the pathological variants of -synuclein have been widely debated, but recent evidence has suggested an emerging consensus on a critical role for -synuclein in regulating synaptic function. However, a controversial role for -synuclein in nuclear function in both normal and pathogenic states has been proposed, and the degree to which -synuclein localizes within the nucleus and subsequent impact on the nucleus are poorly understood. To begin to address this controversy, we employed synucleinopathy murine and cell culture models, as well as postmortem human Lewy Body Dementia tissue to elucidate the extent to which pathological -synuclein localizes within the nuclear compartments, and the downstream consequences of this localization. We observed pathological aggregation of -synuclein within the nucleus in both murine models and human postmortem Lewy Body Dementia cortex via quantitative super resolution microscopy. In both mouse and human brain tissue the presence of -synuclein in the nucleus correlated with abnormal morphology of nuclei. This pathological accumulation of -synuclein in the nucleus was not observed in control mice, human tissue without pathology, or control cells. We subsequently examined the mechanistic consequences of pathological accumulation of -synuclein in the nucleus. Synucleinopathy models displayed increased levels of the DNA damage marker 53BP1. Furthermore, cells with pathological -synuclein exhibited elevated markers of nuclear envelope damage and abnormal expression of nuclear envelope repair markers. Our cell culture data also suggests altered RNA localization in response to pathological -synuclein accumulation within the nucleus. Lastly, we show that nuclear Lewy-like pathology leads to increased sensitivity to nuclear targeted toxins. Taken together, these results rigorously illustrate nuclear localization of pathological -synuclein with super resolution methodology and provide novel insight into the ensuing impact on nuclear integrity and function.

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Millett, M., Comite, A., Castosa, E. M., Heuberger, A., Wagner, P., Gallardo, I., Reinhardt, J., Chambers, N., Hall, D., Miller, E., Nabert, D., Balsamo, B., Prokop, S., Moehle, M.. 2025-03-12. Pathological α-Synuclein Perturbs Nuclear Integrity. https://doi.org/10.1101/2025.03.04.641384

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