Tracing brain genotoxic stress in Parkinson's disease with a novel single-cell genetic sensor

Sci Adv. 2022 Apr 15;8(15):eabd1700. doi: 10.1126/sciadv.abd1700. Epub 2022 Apr 15.


To develop an in vivo tool to probe brain genotoxic stress, we designed a viral proxy as a single-cell genetic sensor termed PRISM that harnesses the instability of recombinant adeno-associated virus genome processing and a hypermutable repeat sequence-dependent reporter. PRISM exploits the virus-host interaction to probe persistent neuronal DNA damage and overactive DNA damage response. A Parkinson's disease (PD)-associated environmental toxicant, paraquat (PQ), inflicted neuronal genotoxic stress sensitively detected by PRISM. The most affected cell type in PD, dopaminergic (DA) neurons in substantia nigra, was distinguished by a high level of genotoxic stress following PQ exposure. Human alpha-synuclein proteotoxicity and propagation also triggered genotoxic stress in nigral DA neurons in a transgenic mouse model. Genotoxic stress is a prominent feature in PD patient brains. Our results reveal that PD-associated etiological factors precipitated brain genotoxic stress and detail a useful tool for probing the pathogenic significance in aging and neurodegenerative disorders.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Brain / metabolism
  • DNA Damage
  • Dopaminergic Neurons / metabolism
  • Humans
  • Mice
  • Mice, Transgenic
  • Paraquat / metabolism
  • Paraquat / toxicity
  • Parkinson Disease* / genetics
  • Parkinson Disease* / metabolism


  • Paraquat