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Posted On: 10/20/2023 10:31:59 PM
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Big new whole-of-university-resources research from Washington University School of Medicine published in Nature (online for now)
MANF stimulates autophagy and restores mitochondrial homeostasis to treat autosomal dominant tubulointerstitial kidney disease in mice
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10576802/
"profound therapeutic potential to ameliorate kidney fibrosis and slow down kidney function decline...In the future, we will continue to test the therapeutic application of MANF as an effective 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 disease47, amyotrophic lateral sclerosis2 and retinitis pigmentosa48, is of great interest for the future investigation."
Misfolded protein aggregates may cause toxic proteinopathy, including autosomal dominant tubulointerstitial kidney disease due to uromodulin mutations (ADTKD-UMOD), a leading hereditary kidney disease. There are no targeted therapies. In our generated mouse model recapitulating human ADTKD-UMOD carrying a leading UMOD mutation, we show that autophagy/mitophagy and mitochondrial biogenesis are impaired, leading to cGAS-STING activation and tubular injury. Moreover, we demonstrate that inducible tubular overexpression of mesencephalic astrocyte-derived neurotrophic factor (MANF), a secreted endoplasmic reticulum protein, after the onset of disease stimulates autophagy/mitophagy, clears mutant UMOD, and promotes mitochondrial biogenesis through p-AMPK enhancement, thus protecting kidney function in our ADTKD mouse model. Conversely, genetic ablation of MANF in the mutant thick ascending limb tubular cells worsens autophagy suppression and kidney fibrosis. Together, we have discovered MANF as a biotherapeutic protein and elucidated previously unknown mechanisms of MANF in the regulation of organelle homeostasis, which may have broad therapeutic applications to treat various proteinopathies.
MANF stimulates autophagy and restores mitochondrial homeostasis to treat autosomal dominant tubulointerstitial kidney disease in mice
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10576802/
"profound therapeutic potential to ameliorate kidney fibrosis and slow down kidney function decline...In the future, we will continue to test the therapeutic application of MANF as an effective 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 disease47, amyotrophic lateral sclerosis2 and retinitis pigmentosa48, is of great interest for the future investigation."
Misfolded protein aggregates may cause toxic proteinopathy, including autosomal dominant tubulointerstitial kidney disease due to uromodulin mutations (ADTKD-UMOD), a leading hereditary kidney disease. There are no targeted therapies. In our generated mouse model recapitulating human ADTKD-UMOD carrying a leading UMOD mutation, we show that autophagy/mitophagy and mitochondrial biogenesis are impaired, leading to cGAS-STING activation and tubular injury. Moreover, we demonstrate that inducible tubular overexpression of mesencephalic astrocyte-derived neurotrophic factor (MANF), a secreted endoplasmic reticulum protein, after the onset of disease stimulates autophagy/mitophagy, clears mutant UMOD, and promotes mitochondrial biogenesis through p-AMPK enhancement, thus protecting kidney function in our ADTKD mouse model. Conversely, genetic ablation of MANF in the mutant thick ascending limb tubular cells worsens autophagy suppression and kidney fibrosis. Together, we have discovered MANF as a biotherapeutic protein and elucidated previously unknown mechanisms of MANF in the regulation of organelle homeostasis, which may have broad therapeutic applications to treat various proteinopathies.
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