{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:52:41Z","timestamp":1782280361037,"version":"3.54.5"},"posted":{"date-parts":[[2025,8,1]]},"group-title":"Neuroscience","reference-count":42,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T00:00:00Z","timestamp":1754006400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"DOI":"10.13039\/100000027","name":"NIAAA","doi-asserted-by":"crossref","award":["AA017226"],"award-info":[{"award-number":["AA017226"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000027","name":"NIAAA","doi-asserted-by":"crossref","award":["AA015407"],"award-info":[{"award-number":["AA015407"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a neurotrophic protein localized in the endoplasmic reticulum (ER) and pivotally involved in maintaining ER homeostasis. MANF plays an important role in mitigating neurodegenerative processes. Aging, the primary risk factor for neurodegenerative diseases (NDDs), is associated with significant alterations in ER function. The ER, central to protein synthesis, folding, degradation and secretion (proteostasis), experiences considerable stress in NDDs, which activates the unfolded protein response (UPR). We hypothesized that MANF and UPR is crucial for maintaining proteostasis during aging, but their efficacy declines with age, therefore increasing vulnerability to NDDs. We measured MANF levels in the brain and plasma of 1-, 4-, 11-, and 22-month-old male and female mice. A progressive decline of MANF levels was observed, with the lowest levels detected in 22 months. Reduced MANF expression was found in aged mice across several brain areas, including the cerebral cortex, olfactory bulb, thalamus, hypothalamus, hippocampus, and cerebellum. There was a sex difference in MANF levels in aged mice. Aging also altered the expression of UPR and MANF interacting proteins. Using cerebellar Purkinje cell (PC)-specific MANF deficient mice, we showed that MANF deficiency impaired motor coordination in female, but not male mice. MANF deficiency weakened spatial learning and memory in both male and female mice. Male MANF deficient mice displayed increased sociability, whereas female mice exhibit social withdrawal. Taken together, MANF expression in the brain declined with age and MANF deficiency impacted neurobehaviors in the aging animal in a sex-specific manner.<\/jats:p>","DOI":"10.1101\/2025.07.29.667462","type":"posted-content","created":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T19:45:29Z","timestamp":1754077529000},"source":"Crossref","is-referenced-by-count":0,"title":["Age-Related Alterations in the Expression of Mesencephalic Astrocyte-derived Neurotrophic Factor in the Brain and Their Impact on Neurobehavioral Functions"],"prefix":"10.64898","author":[{"given":"Di","family":"Hu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuohui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025080514200945000_2025.07.29.667462v1.1","doi-asserted-by":"crossref","unstructured":"Meiseles, D. , N. Arbeli , and M. Dvela-Levitt , When Proteins Go Berserk: The Unfolded Protein Response and ER Stress. Nephron, 2025: p. 1\u201311.","DOI":"10.1159\/000544971"},{"key":"2025080514200945000_2025.07.29.667462v1.2","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2022.831116"},{"key":"2025080514200945000_2025.07.29.667462v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2023.148742"},{"key":"2025080514200945000_2025.07.29.667462v1.4","doi-asserted-by":"crossref","first-page":"765","DOI":"10.3389\/fendo.2019.00765","article-title":"Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) Is Highly Expressed in Mouse Tissues With Metabolic Function","volume":"10","year":"2019","journal-title":"Front Endocrinol (Lausanne"},{"key":"2025080514200945000_2025.07.29.667462v1.5","doi-asserted-by":"crossref","unstructured":"Pakarinen, E. , et al., MANF Ablation Causes Prolonged Activation of the UPR without Neurodegeneration in the Mouse Midbrain Dopamine System. eNeuro, 2020. 7(1).","DOI":"10.1523\/ENEURO.0477-19.2019"},{"issue":"5","key":"2025080514200945000_2025.07.29.667462v1.6","doi-asserted-by":"crossref","first-page":"2992","DOI":"10.1007\/s12035-022-02786-7","article-title":"Potential Role of MANF, an ER Stress Responsive Neurotrophic Factor, in Protecting Against Alcohol Neurotoxicity","volume":"59","year":"2022","journal-title":"Mol Neurobiol"},{"key":"2025080514200945000_2025.07.29.667462v1.7","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2023.1188697"},{"key":"2025080514200945000_2025.07.29.667462v1.8","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.brainresbull.2022.02.019","article-title":"Deficiency of mesencephalic astrocyte-derived neurotrophic factor affects neurogenesis in mouse brain","volume":"183","year":"2022","journal-title":"Brain Res Bull"},{"key":"2025080514200945000_2025.07.29.667462v1.9","doi-asserted-by":"crossref","first-page":"560020","DOI":"10.3389\/fnmol.2020.560020","article-title":"Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) Regulates Neurite Outgrowth Through the Activation of Akt\/mTOR and Erk\/mTOR Signaling Pathways","volume":"13","year":"2020","journal-title":"Front Mol Neurosci"},{"key":"2025080514200945000_2025.07.29.667462v1.10","doi-asserted-by":"crossref","unstructured":"Tseng, K.Y. , et al., MANF Is Essential for Neurite Extension and Neuronal Migration in the Developing Cortex. eNeuro, 2017. 4(5).","DOI":"10.1523\/ENEURO.0214-17.2017"},{"key":"2025080514200945000_2025.07.29.667462v1.11","doi-asserted-by":"publisher","DOI":"10.1385\/JMN:20:2:173"},{"key":"2025080514200945000_2025.07.29.667462v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2008.07.016"},{"key":"2025080514200945000_2025.07.29.667462v1.13","doi-asserted-by":"publisher","DOI":"10.1002\/cne.22039"},{"key":"2025080514200945000_2025.07.29.667462v1.14","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0833-09.2009"},{"key":"2025080514200945000_2025.07.29.667462v1.15","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2009.181"},{"key":"2025080514200945000_2025.07.29.667462v1.16","doi-asserted-by":"crossref","first-page":"112037","DOI":"10.1016\/j.exger.2022.112037","article-title":"Mesencephalic astrocyte-derived neurotrophic factor (MANF) prevents the neuroinflammation induced dopaminergic neurodegeneration","volume":"171","year":"2023","journal-title":"Exp Gerontol"},{"key":"2025080514200945000_2025.07.29.667462v1.17","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0090433"},{"key":"2025080514200945000_2025.07.29.667462v1.18","doi-asserted-by":"crossref","unstructured":"Wen, W. , et al., Spatial Transcriptomics Analysis Uncovers ER stress in MANF-deficient Purkinje Cells Underlying Alcohol-induced Cerebellar Vulnerability in Mice. bioRxiv, 2025: p. 2025.06.19.660571.","DOI":"10.1101\/2025.06.19.660571"},{"key":"2025080514200945000_2025.07.29.667462v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2020.105216"},{"key":"2025080514200945000_2025.07.29.667462v1.20","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2024.1407576"},{"key":"2025080514200945000_2025.07.29.667462v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.100295"},{"issue":"12","key":"2025080514200945000_2025.07.29.667462v1.22","doi-asserted-by":"crossref","first-page":"101810","DOI":"10.1016\/j.isci.2020.101810","article-title":"Neuroplastin Modulates Anti-inflammatory Effects of MANF","volume":"23","year":"2020","journal-title":"iScience"},{"issue":"2","key":"2025080514200945000_2025.07.29.667462v1.23","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1038\/s42255-018-0023-6","article-title":"MANF regulates metabolic and immune homeostasis in ageing and protects against liver damage","volume":"1","year":"2019","journal-title":"Nat Metab"},{"key":"2025080514200945000_2025.07.29.667462v1.24","doi-asserted-by":"crossref","unstructured":"Burmistrov, D.E. , et al., Sex as a Determinant of Age-Related Changes in the Brain. Int J Mol Sci, 2024. 25(13).","DOI":"10.3390\/ijms25137122"},{"key":"2025080514200945000_2025.07.29.667462v1.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2022.104639"},{"issue":"2","key":"2025080514200945000_2025.07.29.667462v1.26","first-page":"802","article-title":"Consensus Paper: Cerebellum and Ageing","volume":"23","year":"2024","journal-title":"Cerebellum"},{"key":"2025080514200945000_2025.07.29.667462v1.27","doi-asserted-by":"crossref","unstructured":"Iskusnykh, I.Y. , et al., Aging, Neurodegenerative Disorders, and Cerebellum. Int J Mol Sci, 2024. 25(2).","DOI":"10.3390\/ijms25021018"},{"issue":"4","key":"2025080514200945000_2025.07.29.667462v1.28","doi-asserted-by":"crossref","first-page":"ar59","DOI":"10.1091\/mbc.E24-01-0012","article-title":"Loss of Grp170 results in catastrophic disruption of endoplasmic reticulum function","volume":"35","year":"2024","journal-title":"Mol Biol Cell"},{"issue":"9","key":"2025080514200945000_2025.07.29.667462v1.29","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1007\/s11064-013-1093-1","article-title":"Tetrandrine attenuated cerebral ischemia\/reperfusion injury and induced differential proteomic changes in a MCAO mice model using 2-D DIGE","volume":"38","year":"2013","journal-title":"Neurochem Res"},{"key":"2025080514200945000_2025.07.29.667462v1.30","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-021-02486-8"},{"issue":"2","key":"2025080514200945000_2025.07.29.667462v1.31","doi-asserted-by":"crossref","first-page":"129338","DOI":"10.1016\/j.bbagen.2019.04.003","article-title":"The Protein Disulfide Isomerase Family: from proteostasis to pathogenesis","volume":"1864","year":"2020","journal-title":"Biochim Biophys Acta Gen Subj"},{"key":"2025080514200945000_2025.07.29.667462v1.32","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2014.01.004"},{"key":"2025080514200945000_2025.07.29.667462v1.33","doi-asserted-by":"publisher","DOI":"10.1080\/14728222.2016.1254197"},{"key":"2025080514200945000_2025.07.29.667462v1.34","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2022.950586"},{"key":"2025080514200945000_2025.07.29.667462v1.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugalcdep.2016.12.028"},{"key":"2025080514200945000_2025.07.29.667462v1.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2023.106258"},{"issue":"5","key":"2025080514200945000_2025.07.29.667462v1.37","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1007\/s12311-024-01706-w","article-title":"Converging and Diverging Cerebellar Pathways for Motor and Social Behaviors in Mice","volume":"23","year":"2024","journal-title":"Cerebellum"},{"key":"2025080514200945000_2025.07.29.667462v1.38","doi-asserted-by":"crossref","unstructured":"Shipman, M.L. and J.T. Green , Cerebellum and cognition: Does the rodent cerebellum participate in cognitive functions? Neurobiol Learn Mem, 2019: p. 106996.","DOI":"10.1016\/j.nlm.2019.02.006"},{"key":"2025080514200945000_2025.07.29.667462v1.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.12.002"},{"issue":"5","key":"2025080514200945000_2025.07.29.667462v1.40","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1038\/s43587-023-00382-5","article-title":"Aging disrupts MANF-mediated immune modulation during skeletal muscle regeneration","volume":"3","year":"2023","journal-title":"Nat Aging"},{"key":"2025080514200945000_2025.07.29.667462v1.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.exger.2020.110893"},{"issue":"4","key":"2025080514200945000_2025.07.29.667462v1.42","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1080\/1061186X.2021.2003803","article-title":"Mesencephalic astrocyte-derived neurotrophic factor restores blood-brain barrier integrity of aged mice after ischaemic stroke\/reperfusion through anti-inflammation via TLR4\/MyD88\/NF-kappaB pathway","volume":"30","year":"2022","journal-title":"J Drug Target"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.07.29.667462","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:01:29Z","timestamp":1782277289000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.07.29.667462"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,1]]},"references-count":42,"URL":"https:\/\/doi.org\/10.1101\/2025.07.29.667462","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1016\/j.mad.2025.112125","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2025,8,1]]},"subtype":"preprint"}}