MANF stimulates autophagy and restores mitochondri
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Posted On: 04/29/2023 1:58:32 AM
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MANF stimulates autophagy and restores mitochondrial homeostasis to treat toxic proteinopathy
https://www.biorxiv.org/content/10.1101/2023....171v1.full
"Misfolded protein aggregates may cause toxic proteinopathy, including autosomal dominant tubulointerstitial kidney disease due to uromodulin mutations (ADTKD-UMOD), one of the leading hereditary kidney diseases, and Alzheimer’s disease etc. There are no targeted therapies. ADTKD is also a genetic form of renal fibrosis and chronic kidney disease, which affects 500 million people worldwide. For the first time, in our newly generated mouse model recapitulating human ADTKD-UMOD carrying a leading UMOD deletion mutation, we show that autophagy/mitophagy and mitochondrial biogenesis are severely impaired, leading to cGAS- STING activation and tubular injury. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a novel endoplasmic reticulum stress-regulated secreted protein. We provide the first study that inducible tubular overexpression of MANF after the onset of disease stimulates autophagy/mitophagy and clearance of the misfolded UMOD, and promotes mitochondrial biogenesis through p-AMPK enhancement, resulting in protection of kidney function. Conversely, genetic ablation of endogenous MANF upregulated in the mutant mouse and human tubular cells worsens autophagy suppression and kidney fibrosis. Together, we discover MANF as a novel biotherapeutic protein and elucidate previously unknown mechanisms of MANF in regulating organelle homeostasis to treat ADTKD, which may have broad therapeutic application to treat various proteinopathies."
"To date, there is no disease-specific therapy to treat or halt the disease progression of ADTKD until the patients reach end-stage renal disease. It has been shown that blocking TNFα- mediated inflammation by using a soluble TNF receptor inhibitor slows disease progression in Umod C147W/+ mice 9. Given the hierarchical order from mitochondrial quality control failure for the eventual activation of proinflammatory cytokines in our deletion mutation mice, we envision that treatment with the upstream p-AMPK enhancer MANF, which can restore homeostasis of dysfunctional mitochondria, might be more effective in ADTKD-UMOD. MANF is an 18kD protein and recombinant MANF is readily available. In the future, we will continue to test the therapeutic application of MANF as a novel strategy for the treatment of ADTKD patients caused by various gene mutations. In addition, whether MANF can treat other proteinopathies resulting from mutant protein aggregates and altered proteostasis, such as Alzheimer’s disease 46, amyotrophic lateral sclerosis 2 and retinitis pigmentosa 47, is of great interest for the future investigation."
https://www.biorxiv.org/content/10.1101/2023....171v1.full
"Misfolded protein aggregates may cause toxic proteinopathy, including autosomal dominant tubulointerstitial kidney disease due to uromodulin mutations (ADTKD-UMOD), one of the leading hereditary kidney diseases, and Alzheimer’s disease etc. There are no targeted therapies. ADTKD is also a genetic form of renal fibrosis and chronic kidney disease, which affects 500 million people worldwide. For the first time, in our newly generated mouse model recapitulating human ADTKD-UMOD carrying a leading UMOD deletion mutation, we show that autophagy/mitophagy and mitochondrial biogenesis are severely impaired, leading to cGAS- STING activation and tubular injury. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a novel endoplasmic reticulum stress-regulated secreted protein. We provide the first study that inducible tubular overexpression of MANF after the onset of disease stimulates autophagy/mitophagy and clearance of the misfolded UMOD, and promotes mitochondrial biogenesis through p-AMPK enhancement, resulting in protection of kidney function. Conversely, genetic ablation of endogenous MANF upregulated in the mutant mouse and human tubular cells worsens autophagy suppression and kidney fibrosis. Together, we discover MANF as a novel biotherapeutic protein and elucidate previously unknown mechanisms of MANF in regulating organelle homeostasis to treat ADTKD, which may have broad therapeutic application to treat various proteinopathies."
"To date, there is no disease-specific therapy to treat or halt the disease progression of ADTKD until the patients reach end-stage renal disease. It has been shown that blocking TNFα- mediated inflammation by using a soluble TNF receptor inhibitor slows disease progression in Umod C147W/+ mice 9. Given the hierarchical order from mitochondrial quality control failure for the eventual activation of proinflammatory cytokines in our deletion mutation mice, we envision that treatment with the upstream p-AMPK enhancer MANF, which can restore homeostasis of dysfunctional mitochondria, might be more effective in ADTKD-UMOD. MANF is an 18kD protein and recombinant MANF is readily available. In the future, we will continue to test the therapeutic application of MANF as a novel strategy for the treatment of ADTKD patients caused by various gene mutations. In addition, whether MANF can treat other proteinopathies resulting from mutant protein aggregates and altered proteostasis, such as Alzheimer’s disease 46, amyotrophic lateral sclerosis 2 and retinitis pigmentosa 47, is of great interest for the future investigation."
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