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Rab10 Phosphorylation Detection by LRRK2 Activity Using SDS-PAGE with a Phosphate-binding Tag
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Parkinson's disease linked LRRK2 G2019S drives oxidative nuclear DNA damage and PARP1 hyperactive signaling

Jennifer Liu1,2, Claudia P Gonzalez-Hunt1,2, Tara Richbourg1,2

  • 1Departments of Neurology and Pathology, Duke University School of Medicine, Durham, North Carolina, 27710, USA.

Biorxiv : the Preprint Server for Biology
|March 27, 2026
PubMed

Insights

Parkinson's disease mutations in LRRK2 cause DNA damage sensitivity. This study reveals a reactive oxygen species (ROS)-dependent pathway involving PARP1 hyperactivation, leading to cellular vulnerability in LRRK2 G2019S cells.

Area of Science:

  • Genetics
  • Neuroscience
  • Molecular Biology

Background:

  • LRRK2 mutations are a primary cause of autosomal-dominant Parkinson's disease (PD).
  • While mitochondrial DNA damage is linked to LRRK2 in PD, nuclear DNA damage mechanisms remain less understood.
  • The G2019S mutation is prevalent in both familial and sporadic PD cases.

Purpose of the Study:

  • To investigate the role of nuclear DNA damage and repair in LRRK2 G2019S-associated Parkinson's disease.
  • To elucidate the molecular mechanisms underlying cellular vulnerability in LRRK2 mutant cells.

Main Methods:

  • CRISPR/Cas9 gene editing to generate LRRK2 G2019S/G2019S knock-in cells.
  • Assessing sensitivity to oxidative and alkylating DNA-damaging agents.
  • Utilizing the oxRADD assay to measure endogenous oxidative nuclear base damage.
  • Analyzing PARP1 activity, poly(ADP-ribose) (PAR) levels, and BER factor recruitment.
  • Investigating cellular responses to PARP-trapping inhibitors and PARP1 knockdown.
  • Evaluating the impact of ROS modulators (EUK-134, rotenone) on PAR accumulation.

Main Results:

  • LRRK2 G2019S/G2019S cells exhibit heightened sensitivity to DNA-damaging agents, indicating impaired base excision repair (BER).
  • Elevated endogenous oxidative nuclear base damage and increased PARP1-dependent PAR levels were observed in mutant cells.
  • PARP1 and BER factors accumulate on chromatin, suggesting BER initiation without resolution.
  • Mutant cells show synthetic lethality with PARP-trapping inhibitors, linked to stabilized PARP-DNA complexes.
  • Reactive oxygen species (ROS) mediate LRRK2 G2019S-dependent PAR accumulation and BER dysfunction.

Conclusions:

  • A novel ROS-dependent PARP1 hyperactivation pathway contributes to cellular vulnerability in LRRK2 G2019S Parkinson's disease.
  • This pathway involves compromised nuclear DNA repair and aberrant PARP1 signaling.
  • Targeting PARP1 or mitigating ROS may offer therapeutic strategies for LRRK2-associated PD.

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