Abstract
BackgroundMesencephalic astrocyte-derived neurotrophic factor (MANF) is a new candidate growth factor for dopaminergic neurons against endoplasmic reticulum stress (ER stress). HSP70 family, a chaperon like heat shock protein family, was proved to be involved in the MANF induced survival pathway in 6-OHDA treated SHSY-5Y cells. However, the ER stress relative transcriptome, in MANF signaling cascades is still investigated. The involvement of HSP70, a 70kd member of HSP70 family, need further to be verified.MethodsThe cell apoptosis was assayed by MTT, TUNEL staining and western blot of cleaved Caspase-3. The differentially expressed genes in SHSY-5Y cells under different conditions (control, 6-OHDA, 6-OHDA + MANF) were investigated by RNA-seq. Expression of HSP70 was further confirmed by real-time PCR. RNAi knockdown for HSP70 was performed to investigate the role of HSP70 in the MANF signaling pathway.ResultsMANF inhibits 6-OHDA-induced apoptosis in SHSY-5Y cells. Six ER stress relative genes (HSP70, GRP78, xbp-1, ATF-4, ATF-6, MAPK) were found enriched in 6-OHDA + MANF treatment group. HSP70 was the most significantly up-regulated gene under 6-OHDA + MANF treatment in SHSY-5Y cells. RNAi knockdown for HSP70 inhibits the protective effects of MANF against 6-OHDA toxicity in SHSY-5Y cells.ConclusionMANF exerts a protective role against 6-OHDA induced apoptosis in SHSY-5Y cells via up-regulating some ER stress genes, including HSP70 family members. The HSP70 expression level plays a key role in MANF-mediated survival pathway.
Highlights
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a new candidate growth factor for dopaminergic neurons against endoplasmic reticulum stress (ER stress)
We found that the expression level of Heat shock protein (HSP70) family, which is considered as a chaperon like heat shock protein family, play key roles in neuroprotection process
We found that MANF inhibited 6OHDA-induced apoptosis in SHSY-5Y cells. 6-OHDA is a neurotoxin widely used to create animal models of Parkinson’s disease (PD)
Summary
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a new candidate growth factor for dopaminergic neurons against endoplasmic reticulum stress (ER stress). Parkinson’s disease (PD) is one of the most common neurodegenerative disorders of the central nervous system. It is characterized by chronic and progressive loss of midbrain dopaminergic (DA) neurons. The newest candidate growth factor for dopaminergic neurons is mesencephalic astrocyte-derived neurotrophic factor (MANF), a kind of evolutionarily conserved neurotrophic factor. It was described few years ago as a survival promoting factor for embryonic midbrain dopaminergic neurons in vitro [1]. The protective effect of MANF is specific for dopaminergic neurons, and no effects on GABAergic or serotonergic neurons are detected [1]
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