Astrocytic expression of Parkinson's disease-related A53T -synuclein causes neurodegeneration in mice

Xing Long Gu, Cai Xia Long, Lixin Sun, Chengsong Xie, Xian Lin, Huaibin Cai

Research output: Contribution to journalArticlepeer-review

158 Scopus citations


Background. Parkinson's disease (PD) is the most common movement disorder. While neuronal deposition of -synuclein serves as a pathological hallmark of PD and Dementia with Lewy Bodies, -synuclein-positive protein aggregates are also present in astrocytes. The pathological consequence of astrocytic accumulation of -synuclein, however, is unclear. Results. Here we show that PD-related A53T mutant -synuclein, when selectively expressed in astrocytes, induced rapidly progressed paralysis in mice. Increasing accumulation of -synuclein aggregates was found in presymptomatic and symptomatic mouse brains and correlated with the expansion of reactive astrogliosis. The normal function of astrocytes was compromised as evidenced by cerebral microhemorrhage and down-regulation of astrocytic glutamate transporters, which also led to increased inflammatory responses and microglial activation. Interestingly, the activation of microglia was mainly detected in the midbrain, brainstem and spinal cord, where a significant loss of dopaminergic and motor neurons was observed. Consistent with the activation of microglia, the expression level of cyclooxygenase 1 (COX-1) was significantly up-regulated in the brain of symptomatic mice and in cultured microglia treated with conditioned medium derived from astrocytes over-expressing A53T -synuclein. Consequently, the suppression of COX-1 activities extended the survival of mutant mice, suggesting that excess inflammatory responses elicited by reactive astrocytes may contribute to the degeneration of neurons. Conclusions. Our findings demonstrate a critical involvement of astrocytic -synuclein in initiating the non-cell autonomous killing of neurons, suggesting the viability of reactive astrocytes and microglia as potential therapeutic targets for PD and other neurodegenerative diseases.

Original languageEnglish (US)
Article number12
JournalMolecular Brain
Issue number1
StatePublished - 2010
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience


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