The role of autophagy dysregulation in manganese-induced dopaminergic neurodegeneration

Jianbin Zhang, Rui Cao, Tongjian Cai, Michael Aschner, Fang Zhao, Ting Yao, Yaoming Chen, Zipeng Cao, Wenjing Luo, Jingyuan Chen

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

The etiological role of dysregulated autophagy in neurodegenerative diseases has been a subject of intense investigation. While manganese (Mn) is known to cause dopaminergic (DAergic) neurodegeneration, it has yet to be determined whether the dysregulation of autophagy plays a role in Mn-induced neuronal injury. In this study, we investigated the effect of Mn on autophagy in a rat model of manganism, a neurodegenerative disease associated with excessive exposure to Mn. After a single intrastriatal injection of Mn, the short- (4-12 h) and long-term (1-28 days) effect of Mn on DAergic neurons and autophagy were examined. Marked reduction in the number of TH-immunoreactive neurons in the substantia nigra pars compacta (SNpc) as well as TH protein expression, and a significant increase of apomorphine-induced rotations were observed in rats after Mn injection. Manganese also induced the down-regulation of dopamine levels and D1 dopamine receptor expression. In addition, autophagy was dysregulated and inhibited, as evidenced by increased number of abnormal lysosomes, decreased protein expression of Beclin1, and decreased ratio of microtubule-associated protein 1 light chain 3 (LC3) II over LC3 I, concomitant with activated mammalian target of rapamycin (mTOR)/p70 ribosomal protein S6 kinase (p70s6k) signaling. In contrast, in the early phase of Mn exposure, the level of autophagy was not be suppressed but compensatorily activated. Although the morphology of the DAergic neuron was intact in the early phase, Mn caused a significant decrease in TH-immunoreactivity and a significant increase in apomorphine-induced rotations in the presence of wortmannin, an inhibitor of autophagy. Taken together, these results demonstrate, for the first time, that autophagy may play a protective role against Mn-induced neuronal damage, whilst dysregulation of autophagy at later phases may mediate DAergic neurodegeneration.

Original languageEnglish (US)
Pages (from-to)478-490
Number of pages13
JournalNeurotoxicity Research
Volume24
Issue number4
DOIs
StatePublished - 2013
Externally publishedYes

Fingerprint

Autophagy
Manganese
Neurodegenerative diseases
Neurons
Apomorphine
Dopaminergic Neurons
Neurodegenerative Diseases
Rats
Ribosomal Protein S6 Kinases
Light
Dopamine D1 Receptors
Injections
Microtubule-Associated Proteins
Sirolimus
Lysosomes
Dopamine
Proteins
Down-Regulation

Keywords

  • Autophagy
  • Beclin 1
  • Dopaminergic neuron
  • Manganese

ASJC Scopus subject areas

  • Neuroscience(all)
  • Toxicology

Cite this

The role of autophagy dysregulation in manganese-induced dopaminergic neurodegeneration. / Zhang, Jianbin; Cao, Rui; Cai, Tongjian; Aschner, Michael; Zhao, Fang; Yao, Ting; Chen, Yaoming; Cao, Zipeng; Luo, Wenjing; Chen, Jingyuan.

In: Neurotoxicity Research, Vol. 24, No. 4, 2013, p. 478-490.

Research output: Contribution to journalArticle

Zhang, J, Cao, R, Cai, T, Aschner, M, Zhao, F, Yao, T, Chen, Y, Cao, Z, Luo, W & Chen, J 2013, 'The role of autophagy dysregulation in manganese-induced dopaminergic neurodegeneration', Neurotoxicity Research, vol. 24, no. 4, pp. 478-490. https://doi.org/10.1007/s12640-013-9392-5
Zhang, Jianbin ; Cao, Rui ; Cai, Tongjian ; Aschner, Michael ; Zhao, Fang ; Yao, Ting ; Chen, Yaoming ; Cao, Zipeng ; Luo, Wenjing ; Chen, Jingyuan. / The role of autophagy dysregulation in manganese-induced dopaminergic neurodegeneration. In: Neurotoxicity Research. 2013 ; Vol. 24, No. 4. pp. 478-490.
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