Astrocytic expression of Parkinson's disease-related A53T alpha-synuclein causes neurodegeneration in mice.
BACKGROUND
Parkinson's disease (PD) is the most common movement disorder. While neuronal deposition of alpha-synuclein serves as a pathological hallmark of PD and Dementia with Lewy Bodies, alpha-synuclein-positive protein aggregates are also present in astrocytes. The pathological consequence of astrocytic accumulation of alpha-synuclein, however, is unclear.


RESULTS
Here we show that PD-related A53T mutant alpha-synuclein, when selectively expressed in astrocytes, induced rapidly progressed paralysis in mice. Increasing accumulation of alpha-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 alpha-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 alpha-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.
Gu
Xing-Long
XL
Units of Transgenesis, Laboratory of Neurogenetics, National Institute on Aging, National Institute of Health, Bethesda, Maryland 20892, USA.
Long
Cai-Xia
CX
Sun
Lixin
L
Xie
Chengsong
C
Lin
Xian
X
Cai
Huaibin
H
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000502:physiology*; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D009483:Neuropsychological Tests; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism
D051844:alpha-Synuclein
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