ArticleCell death & disease2020
Deficiency of the ER-stress-regulator MANF triggers progressive outer hair cell death and hearing loss.
Article in Cell death & disease, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 54 citations in OpenAlex.
- Designing chemigenetic DNA nanotrap for norepinephrine dynamic imaging in organelles.Nature chemical biology · 2026Article
- Regulatory Networks Driving the Specification, Differentiation, and Diversification of Neurons in the Mouse Inner Ear.Journal of the Association for Research in Otolaryngology : JARO · 2026Review
- Cross-species validation of a human age-related hearing loss candidate KLHDC7B as essential for mammalian hearing.Communications biology · 2025Article
- Ototoxic impacts of adipose-derived extracts on a murine auditory cell line: molecular insights from proteomic analyses.International journal of obesity (2005) · 2025Article
- Presbycusis: Pathology, Signal Pathways, and Therapeutic Strategy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- Mutations in unfolded protein response regulator ATF6 cause hearing and vision loss syndrome.The Journal of clinical investigation · 2025Article
- Emerging role of IRE1α in vascular diseases.Journal of cell communication and signaling · 2024Review
- GRP78 protein metabolism in obese and diabetic rats: a study of its role in metabolic disorders.Diabetology & metabolic syndrome · 2024Article
- Insights into the molecular underlying mechanisms and therapeutic potential of endoplasmic reticulum stress in sensorineural hearing loss.Frontiers in molecular neuroscience · 2024Review
- Navigating the Landscape of MANF Research: A Scientometric Journey with CiteSpace Analysis.Cellular and molecular neurobiology · 2023Review
- Aging disrupts MANF-mediated immune modulation during skeletal muscle regeneration.Nature aging · 2023Article
- Ginsenoside Rc from Panax Ginseng Ameliorates Palmitate-Induced UB/OC-2 Cochlear Cell Injury.International journal of molecular sciences · 2023Article
- Early Steps towards Hearing: Placodes and Sensory Development.International journal of molecular sciences · 2023Review
- CDNF and MANF in the brain dopamine system and their potential as treatment for Parkinson's disease.Frontiers in psychiatry · 2023Review
- ISL1 is necessary for auditory neuron development and contributes toward tonotopic organization.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Endoplasmic Reticulum in Metaplasticity: From Information Processing to Synaptic Proteostasis.Molecular neurobiology · 2022Review
- Tripartite motif 25 ameliorates doxorubicin-induced cardiotoxicity by degrading p85α.Cell death & disease · 2022Article
- Potential Role of MANF, an ER Stress Responsive Neurotrophic Factor, in Protecting Against Alcohol Neurotoxicity.Molecular neurobiology · 2022Review
- Cerebral dopamine neurotrophic factor protects and repairs dopamine neurons by novel mechanism.Molecular psychiatry · 2022Review
- CDNF and MANF regulate ER stress in a tissue-specific manner.Cellular and molecular life sciences : CMLS · 2022Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
The non-conventional neurotrophic factor mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-resident protein that promotes ER homeostasis. MANF has a cytoprotective function, shown in the central nervous system neurons and pancreatic beta cells. Here, we report that MANF is expressed in the hair cells and neurons and in selected non-sensory cells of the cochlea and that Manf inactivation triggers upregulation of the ER chaperones in these cells. However, Manf inactivation resulted in the death of only outer hair cells (OHCs), the cells responsible for sound amplification in the cochlea. All OHCs were formed in Manf-inactivated mice, but progressive OHC death started soon after the onset of hearing function. The robust OHC loss was accompanied by strongly elevated hearing thresholds. Conditional Manf inactivation demonstrated that MANF has a local function in the cochlea. Immunostainings revealed the upregulation of CHOP, the pro-apoptotic component of the unfolded protein response (UPR), in Manf-inactivated OHCs, linking the UPR to the loss of these cells. The phenotype of Manf-inactivated OHCs was distinctly dependent on the mouse strain, such that the strains characterized by early-onset age-related hearing loss (C57BL/6J and CD-1) were affected. These results suggest that Manf deficiency becomes detrimental when accompanied by gene mutations that predispose to hearing loss, by intensifying ER dyshomeostasis. Together, MANF is the first growth factor shown to antagonize ER stress-mediated OHC death. MANF might serve as a therapeutic candidate for protection against hearing loss induced by the ER-machinery-targeting stressors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.