Alpha-synuclein is a DNA binding protein that modulates DNA repair with implications for Lewy body disorders

Allison J. Schaser, Valerie R. Osterberg, Sydney E. Dent, Teresa L. Stackhouse, Colin M. Wakeham, Sydney W. Boutros, Leah J. Weston, Nichole Owen, Tamily A. Weissman, Esteban Luna, Jacob Raber, Kelvin C. Luk, Amanda McCullough, Randall (Randy) Woltjer, Vivek Unni

Research output: Contribution to journalArticle

Abstract

Alpha-synuclein is a presynaptic protein that forms abnormal cytoplasmic aggregates in Lewy body disorders. Although nuclear alpha-synuclein localization has been described, its function in the nucleus is not well understood. We demonstrate that alpha-synuclein modulates DNA repair. First, alpha-synuclein colocalizes with DNA damage response components within discrete foci in human cells and mouse brain. Removal of alpha-synuclein in human cells leads to increased DNA double-strand break (DSB) levels after bleomycin treatment and a reduced ability to repair these DSBs. Similarly, alpha-synuclein knock-out mice show increased neuronal DSBs that can be rescued by transgenic reintroduction of human alpha-synuclein. Alpha-synuclein binds double-stranded DNA and helps to facilitate the non-homologous end-joining reaction. Using a new, in vivo imaging approach that we developed, we find that serine-129-phosphorylated alpha-synuclein is rapidly recruited to DNA damage sites in living mouse cortex. We find that Lewy inclusion-containing neurons in both mouse model and human-derived patient tissue demonstrate increased DSB levels. Based on these data, we propose a model whereby cytoplasmic aggregation of alpha-synuclein reduces its nuclear levels, increases DSBs, and may contribute to programmed cell death via nuclear loss-of-function. This model could inform development of new treatments for Lewy body disorders by targeting alpha-synuclein-mediated DNA repair mechanisms.

Original languageEnglish (US)
Article number10919
JournalScientific Reports
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2019

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Lewy Bodies
alpha-Synuclein
DNA-Binding Proteins
DNA Repair
DNA Damage
Double-Stranded DNA Breaks
Bleomycin
Knockout Mice
Serine
Cell Death
Neurons

ASJC Scopus subject areas

  • General

Cite this

Schaser, A. J., Osterberg, V. R., Dent, S. E., Stackhouse, T. L., Wakeham, C. M., Boutros, S. W., ... Unni, V. (2019). Alpha-synuclein is a DNA binding protein that modulates DNA repair with implications for Lewy body disorders. Scientific Reports, 9(1), [10919]. https://doi.org/10.1038/s41598-019-47227-z

Alpha-synuclein is a DNA binding protein that modulates DNA repair with implications for Lewy body disorders. / Schaser, Allison J.; Osterberg, Valerie R.; Dent, Sydney E.; Stackhouse, Teresa L.; Wakeham, Colin M.; Boutros, Sydney W.; Weston, Leah J.; Owen, Nichole; Weissman, Tamily A.; Luna, Esteban; Raber, Jacob; Luk, Kelvin C.; McCullough, Amanda; Woltjer, Randall (Randy); Unni, Vivek.

In: Scientific Reports, Vol. 9, No. 1, 10919, 01.12.2019.

Research output: Contribution to journalArticle

Schaser, AJ, Osterberg, VR, Dent, SE, Stackhouse, TL, Wakeham, CM, Boutros, SW, Weston, LJ, Owen, N, Weissman, TA, Luna, E, Raber, J, Luk, KC, McCullough, A, Woltjer, RR & Unni, V 2019, 'Alpha-synuclein is a DNA binding protein that modulates DNA repair with implications for Lewy body disorders', Scientific Reports, vol. 9, no. 1, 10919. https://doi.org/10.1038/s41598-019-47227-z
Schaser, Allison J. ; Osterberg, Valerie R. ; Dent, Sydney E. ; Stackhouse, Teresa L. ; Wakeham, Colin M. ; Boutros, Sydney W. ; Weston, Leah J. ; Owen, Nichole ; Weissman, Tamily A. ; Luna, Esteban ; Raber, Jacob ; Luk, Kelvin C. ; McCullough, Amanda ; Woltjer, Randall (Randy) ; Unni, Vivek. / Alpha-synuclein is a DNA binding protein that modulates DNA repair with implications for Lewy body disorders. In: Scientific Reports. 2019 ; Vol. 9, No. 1.
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