MANF protects dopamine neurons and locomotion defects from a human α-synuclein induced Parkinson's disease model in C. elegans by regulating ER stress and autophagy pathways

Zhang, Zhuoyu; Shen, Yijue; Luo, Hang; Zhang, Fen; Peng, Dan; Li, Jing; Wu, Yuanyuan; Xia, Xiaofei; Song, Yunping; Li, Wei; Jin, Lingjing

doi:10.1016/j.expneurol.2018.06.016

Cited by 44 publications

(31 citation statements)

References 57 publications

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“…It appears that H. mephisto has developed different genomic strategies for upregulating these two genes: mild upregulation of many paralogous genes (Hsp70) versus extremely highly induced expression of a single-copy gene (ARMET). Regardless, ARMET is a strong marker of ER stress with cytoprotective roles 58,60,61 .…”

Section: Resultsmentioning

confidence: 99%

The genome of a subterrestrial nematode reveals adaptations to heat

et al. 2019

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The nematode Halicephalobus mephisto was originally discovered inhabiting a deep terrestrial aquifer 1.3 km underground. H. mephisto can thrive under conditions of abiotic stress including heat and minimal oxygen, where it feeds on a community of both chemolithotrophic and heterotrophic prokaryotes in an unusual ecosystem isolated from the surface biosphere. Here we report the comprehensive genome and transcriptome of this organism, identifying a signature of adaptation: an expanded repertoire of 70 kilodalton heat-shock proteins (Hsp70) and avrRpt2 induced gene 1 (AIG1) proteins. The expanded Hsp70 genes are transcriptionally induced upon growth under heat stress, and we find that positive selection is detectable in several members of this family. We further show that AIG1 may have been acquired by horizontal gene transfer (HGT) from a rhizobial fungus. Over one-third of the genes of H. mephisto are novel, highlighting the divergence of this nematode from other sequenced organisms. This work sheds light on the genomic basis of heat tolerance in a complete subterrestrial eukaryotic genome.

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Section: Resultsmentioning

confidence: 99%

The genome of a subterrestrial nematode reveals adaptations to heat

et al. 2019

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“…Another recent study suggested that MANF can regulate energy homeostasis, as transgenic overexpression of MANF in the brain hypothalamus led to overfeeding and obesity in mice 35 . In light of these new findings, and together with previous studies that have shown protective effects of MANF in animal models of neurodegenerative diseases 9,12–14 , we first aimed to determine if MANF is also induced upon health-promoting dietary restriction in humans. We examined the effects of therapeutic fasting on concentrations of circulating MANF and analysed correlations between MANF and clinical variables to reveal possible mechanisms related to the regulation of circulating MANF levels.…”

Section: Discussionmentioning

confidence: 99%

“…MANF (also known as ARMET) was originally identified based on its survival-promoting activity on cultured brain dopamine neurons 8 . Since then, the protective properties of MANF on various cell types have been demonstrated in animal models of Parkinson’s disease, cerebral ischemia, spinocerebellar ataxia, myocardial infarction, and retinal degeneration 9–14 . Manf conventional knock-out mice develop insulin-dependent diabetes due to postnatal loss of pancreatic insulin-producing beta cell mass, indicating that MANF is important for the function and maintenance of pancreatic beta cells 15 .…”

Section: Introductionmentioning

confidence: 99%

Mesencephalic Astrocyte-Derived Neurotrophic Factor Is Upregulated with Therapeutic Fasting in Humans and Diet Fat Withdrawal in Obese Mice

Galli

Rossi

Neumann

et al. 2019

Sci Rep

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Dietary restriction induces beneficial metabolic changes and prevents age-related deterioration. Mesencephalic astrocyte-derived neurotrophic factor (MANF) shows protective effects on cells in various models of degenerative diseases. Here we studied whether circulating concentrations of MANF are associated with fasting-induced positive effects. We quantified the levels of circulating MANF from 40 human subjects before and after therapeutic fasting. As measured by an enzyme-linked immunosorbent assay (ELISA), the mean concentration of plasma MANF increased after an average fasting of 15 days. Plasma MANF levels correlated inversely with adiponectin, a hormone that regulates metabolism, thus suggesting that MANF levels are related to metabolic homeostasis. To study the effects of dietary intervention on MANF concentrations in mice, we developed an ELISA for mouse MANF and verified its specificity using MANF knock-out (KO) tissue. A switch from high-fat to normal diet increased MANF levels and downregulated the expression of unfolded protein response (UPR) genes in the liver, indicating decreased endoplasmic reticulum (ER) stress. Liver MANF and serum adiponectin concentrations correlated inversely in mice. Our findings demonstrate that MANF expression and secretion increases with dietary intervention. The MANF correlation to adiponectin and its possible involvement in metabolic regulation and overall health warrants further studies.

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“…The closely related trophic factors mesencephalic astrocyte-derived neurotrophic factor (MANF) (Petrova et al, 2003) and cerebral/conserved dopamine neurotrophic factor (CDNF) (Lindholm et al, 2007) similarly provide neuroprotection in various animal models of PD (Airavaara et al, 2012). The exact mode of action of these proteins is unknown, although neuroprotection seems to be, at least in part, conferred via modulation of endoplasmic reticulum stress and autophagy (Zhang et al, 2018). A clinical trial is currently ongoing (ClinicalTrials.gov Identifier: NCT03775538) assessing the safety of putamenal delivery of CDNF (Huttunen and Saarma, 2019) and anecdotal reports suggests that the treatment has been well-tolerated.…”

Section: Alternatives To Gflsmentioning

confidence: 99%