Conditional Haploinsufficiency of β-Catenin Aggravates Neuronal Damage in a Paraquat-Based Mouse Model of Parkinson Disease

Abstract

The canonical Wnt pathway is critical for both the development and adulthood survival and homeostatic maintenance of the midbrain dopaminergic (DA) neurons. Expanding evidence has demonstrated that genetic factors associated with familial Parkinson disease (PD) deregulate this important pathway, suggesting that a disturbed canonical Wnt pathway is likely involved in PD pathogenesis; yet, the specific role of this pathway in sporadic PD remains unclear. In this study, we aimed to determine the effects of specific inhibition of the canonical pathway by hemizygous knockout of β-catenin, the obligatory component of the canonical Wnt pathway, on paraquat (PQ)-induced DA neuronal degeneration in the substantia nigra in vivo. We found that while hemizygous conditional knockout of β-catenin in DA neurons did not cause any significant TH+ neuronal loss in the substantia nigra at basal level, it triggered elevated oxidative stress at basal level and further enhanced PQ-induced oxidative damage and loss of TH+ neurons in the substantia nigra and axonal termini in the striatum that manifested as exacerbated motor deficits. These data support the notion that reduced Wnt/β-catenin signaling in sporadic PD likely contributes to DA neuronal loss through an enhanced oxidative stress-response pathway.

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Abbreviations

DA:

Dopaminergic

DAT:

Dopamine transporter

4-HNE:

4-Hydroxynonenal

JNKs:

c-Jun N-terminal kinases

KO:

Knockout

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

PQ:

Paraquat

PD:

Parkinson disease

ROS:

Reactive oxygen species

SN:

Substantia nigra pars compacta

TH:

Tyrosine hydroxylase

Tg:

Transgenic

VTA:

Ventral tegmental

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Funding

This research was partly supported by the National Institute of Health [grant number NS083498 (to X. Zhu)], the Dr. Robert M. Kohrman Memorial Fund (to X. Zhu), the National Natural Science Foundation of China [No. 81430023 (to B. Tang)], the National Key Plan for Scientific Research and Development of China [No. 2016YFC1306000 (to B. Tang)], and the NSFC-NIH joint program [No. 81361120404 (to B. Tang)].

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FZ designed/carried out experiments, collected data and wrote the manuscript, SLS, SLR QX, BT contributed to interpretation of results and provided feedback on the manuscript. BT and XZ conceived the project. XZ directed the project, interpret results and wrote the manuscript. All authors had final approval of the submitted version.

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Correspondence to Beisha Tang or Xiongwei Zhu.

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Zhao, F., Siedlak, S.L., Torres, S.L. et al. Conditional Haploinsufficiency of β-Catenin Aggravates Neuronal Damage in a Paraquat-Based Mouse Model of Parkinson Disease. Mol Neurobiol 56, 5157–5166 (2019). https://doi.org/10.1007/s12035-018-1431-z

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Keywords

  • Parkinson disease
  • Canonical Wnt pathway
  • β-Catenin
  • Oxidative stress
  • Neurodegeneration