{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T01:08:30Z","timestamp":1779239310113,"version":"3.51.4"},"reference-count":62,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2025,1,13]],"date-time":"2025-01-13T00:00:00Z","timestamp":1736726400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,1,13]],"date-time":"2025-01-13T00:00:00Z","timestamp":1736726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["No.81974211"],"award-info":[{"award-number":["No.81974211"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["No.82171247"],"award-info":[{"award-number":["No.82171247"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["No.82371433"],"award-info":[{"award-number":["No.82371433"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Scientific Research and Innovation Team of The First Affiliated Hospital of Zhengzhou University","award":["No.ZYCXTD2023011"],"award-info":[{"award-number":["No.ZYCXTD2023011"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["EMBO J"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The carboxyl terminus of Hsc70-interacting protein (CHIP) is pivotal for managing misfolded and aggregated proteins via chaperone networks and degradation pathways. In a preclinical rodent model of CHIP-related ataxia, we observed that CHIP mutations lead to increased levels of phosphodiesterase 9A (PDE9A), whose role in this context remains poorly understood. Here, we investigated the molecular mechanisms underlying the role of PDE9A in CHIP-related ataxia and demonstrated that CHIP binds to PDE9A, facilitating its polyubiquitination and autophagic degradation. Conversely, dysfunctional CHIP disrupts this process, resulting in PDE9A accumulation, increased cGMP hydrolysis, and impaired PKG phosphorylation of CHIP at serine 19. This cascade further amplifies PDE9A accumulation, ultimately disrupting mitophagy and triggering neuronal apoptosis. Elevated PKA levels inhibit PDE9A degradation, further exacerbating this neuronal dysfunction. Notably, pharmacological inhibition of PDE9A via Bay 73-6691 or virus-mediated CHIP expression restored the balance of cGMP\/cAMP signalling. These interventions protect against cerebellar neuropathologies, particularly Purkinje neuron mitophagy dysfunction. Thus, PDE9A upregulation considerably exacerbates ataxia associated with CHIP mutations, and targeting the interaction between PDE9A and CHIP is an innovative therapeutic strategy for CHIP-related ataxia.<\/jats:p>","DOI":"10.1038\/s44318-024-00351-7","type":"journal-article","created":{"date-parts":[[2025,1,13]],"date-time":"2025-01-13T06:50:49Z","timestamp":1736751049000},"page":"1249-1273","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A"],"prefix":"10.1038","volume":"44","author":[{"given":"Xiaoyan","family":"Hao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhengwei","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mengjie","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuo","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mibo","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenwei","family":"Hao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shasha","family":"Qi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuanyuan","family":"Liang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0188-2717","authenticated-orcid":false,"given":"Michael F","family":"Almeida","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4907-2342","authenticated-orcid":false,"given":"Kaitlan","family":"Smith","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunyan","family":"Zuo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanmei","family":"Feng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mengnan","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dongrui","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4033-9869","authenticated-orcid":false,"given":"Shuangjie","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiyun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuemeng","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhifen","family":"Deng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chengyuan","family":"Mao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zongping","family":"Xia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8087-5717","authenticated-orcid":false,"given":"Yong","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanxia","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2689-9897","authenticated-orcid":false,"given":"Yuming","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7382-2783","authenticated-orcid":false,"given":"Jonathan C","family":"Schisler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4843-0072","authenticated-orcid":false,"given":"Changhe","family":"Shi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,1,13]]},"reference":[{"key":"351_CR1","doi-asserted-by":"crossref","DOI":"10.1212\/WNL.0000000000209131","volume":"102","author":"M Adesuyan","year":"2024","unstructured":"Adesuyan M, Jani YH, Alsugeir D, Howard R, Ju C, Wei L, Brauer R (2024) Phosphodiesterase type 5 inhibitors in men with erectile dysfunction and the risk of Alzheimer disease: a cohort study. Neurology 102:e209131","journal-title":"Neurology"},{"key":"351_CR2","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.neubiorev.2020.02.004","volume":"113","author":"EK Argyrousi","year":"2020","unstructured":"Argyrousi EK, Heckman PR, Prickaerts J (2020) Role of cyclic nucleotides and their downstream signaling cascades in memory function: Being at the right time at the right spot. Neurosci Biobehav Rev 113:12\u201338","journal-title":"Neurosci Biobehav Rev"},{"key":"351_CR3","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1016\/j.tibs.2006.10.002","volume":"31","author":"JL Bos","year":"2006","unstructured":"Bos JL (2006) Epac proteins: multi-purpose cAMP targets. Trends Biochem Sci 31:680\u2013686","journal-title":"Trends Biochem Sci"},{"key":"351_CR4","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1161\/CIRCULATIONAHA.114.009751","volume":"130","author":"KJ Bubb","year":"2014","unstructured":"Bubb KJ, Trinder SL, Baliga RS, Patel J, Clapp LH, MacAllister RJ, Hobbs AJ (2014) Inhibition of phosphodiesterase 2 augments cGMP and cAMP signaling to ameliorate pulmonary hypertension. Circulation 130:496\u2013507","journal-title":"Circulation"},{"key":"351_CR5","doi-asserted-by":"crossref","first-page":"2910","DOI":"10.1016\/j.cub.2018.07.062","volume":"28","author":"RA Carter","year":"2018","unstructured":"Carter RA, Bihannic L, Rosencrance C, Hadley JL, Tong Y, Phoenix TN, Natarajan S, Easton J, Northcott PA, Gawad C (2018) A single-cell transcriptional atlas of the developing murine cerebellum. Curr Biol 28:2910\u20132920.e2912","journal-title":"Curr Biol"},{"key":"351_CR6","doi-asserted-by":"crossref","unstructured":"Chakraborty A, Edkins AL (2022) CHIP: a co-chaperone for degradation by the proteasome and lysosome. In: The networking of chaperones by co-chaperones. pp 351\u2013387","DOI":"10.1007\/978-3-031-14740-1_12"},{"key":"351_CR7","volume":"11","author":"B-H Chen","year":"2020","unstructured":"Chen B-H, Chang Y-J, Lin S, Yang WY (2020) Hsc70\/Stub1 promotes the removal of individual oxidatively stressed peroxisomes. Nat Commun 11:5267","journal-title":"Nat Commun"},{"key":"351_CR8","doi-asserted-by":"crossref","first-page":"101130","DOI":"10.1016\/j.gendis.2023.101130","volume":"11","author":"S Cuinat","year":"2023","unstructured":"Cuinat S, B\u00e9zieau S, Deb W, Mercier S, Vignard V, Isidor B, K\u00fcry S, Ebstein F (2023) Understanding neurodevelopmental proteasomopathies as new rare disease entities: a review of current concepts, molecular biomarkers, and perspectives. Genes Dis 11:101130","journal-title":"Genes Dis"},{"key":"351_CR9","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1080\/15548627.2017.1402992","volume":"14","author":"V Deretic","year":"2018","unstructured":"Deretic V, Levine B (2018) Autophagy balances inflammation in innate immunity. Autophagy 14:243\u2013251","journal-title":"Autophagy"},{"key":"351_CR10","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/nbt.3440","volume":"34","author":"BE Deverman","year":"2016","unstructured":"Deverman BE, Pravdo PL, Simpson BP, Kumar SR, Chan KY, Banerjee A, Wu WL, Yang B, Huber N, Pasca SP et al (2016) Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain. Nat Biotechnol 34:204\u2013209","journal-title":"Nat Biotechnol"},{"key":"351_CR11","doi-asserted-by":"crossref","first-page":"61","DOI":"10.3390\/ph14010061","volume":"14","author":"E Fedele","year":"2021","unstructured":"Fedele E, Ricciarelli R (2021) Memory enhancers for Alzheimer\u2019s dementia: focus on cGMP. Pharmaceuticals 14:61","journal-title":"Pharmaceuticals"},{"key":"351_CR12","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.4161\/auto.25190","volume":"9","author":"JV Ferreira","year":"2013","unstructured":"Ferreira JV, Fofo H, Bejarano E, Bento CF, Ramalho JS, Girao H, Pereira P (2013) STUB1\/CHIP is required for HIF1A degradation by chaperone-mediated autophagy. Autophagy 9:1349\u20131366","journal-title":"Autophagy"},{"key":"351_CR13","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/S0022-5223(19)37950-4","volume":"79","author":"W Flameng","year":"1980","unstructured":"Flameng W, Borgers M, Daenen W, Stalpaert G (1980) Ultrastructural and cytochemical correlates of myocardial protection by cardiac hypothermia in man. J Thorac Cardiovasc Surg 79:413\u2013424","journal-title":"J Thorac Cardiovasc Surg"},{"key":"351_CR14","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1038\/nbt.4259","volume":"36","author":"I Gupta","year":"2018","unstructured":"Gupta I, Collier PG, Haase B, Mahfouz A, Joglekar A, Floyd T, Koopmans F, Barres B, Smit AB, Sloan SA (2018) Single-cell isoform RNA sequencing characterizes isoforms in thousands of cerebellar cells. Nat Biotechnol 36:1197\u20131202","journal-title":"Nat Biotechnol"},{"key":"351_CR15","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1016\/j.drudis.2007.07.023","volume":"12","author":"TB Halene","year":"2007","unstructured":"Halene TB, Siegel SJ (2007) PDE inhibitors in psychiatry\u2013future options for dementia, depression and schizophrenia? Drug Discov today 12:870\u2013878","journal-title":"Drug Discov today"},{"key":"351_CR16","doi-asserted-by":"crossref","DOI":"10.3389\/fcell.2022.837337","volume":"10","author":"CT Jetto","year":"2022","unstructured":"Jetto CT, Nambiar A, Manjithaya R (2022) Mitophagy and neurodegeneration: between the knowns and the unknowns. Front Cell Dev Biol 10:837337","journal-title":"Front Cell Dev Biol"},{"key":"351_CR17","doi-asserted-by":"crossref","DOI":"10.1016\/j.arr.2024.102279","volume":"96","author":"A Kaushik","year":"2024","unstructured":"Kaushik A, Parashar S, Ambasta RK, Kumar P (2024) Ubiquitin E3 ligases assisted technologies in protein degradation: Sharing Pathways in Neurodegenerative Disorders and Cancer. Ageing Res Rev 96:102279","journal-title":"Ageing Res Rev"},{"key":"351_CR18","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1016\/j.neuron.2022.12.012","volume":"111","author":"J Kim","year":"2023","unstructured":"Kim J, de Haro M, Al-Ramahi I, Garaicoechea LL, Jeong H-H, Sonn JY, Tadros B, Liu Z, Botas J, Zoghbi HY (2023) Evolutionarily conserved regulators of tau identify targets for new therapies. Neuron 111:824\u2013838.e827","journal-title":"Neuron"},{"key":"351_CR19","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1016\/j.gendis.2021.08.003","volume":"9","author":"S Kumar","year":"2022","unstructured":"Kumar S, Basu M, Ghosh MK (2022) Chaperone-assisted E3 ligase CHIP: a double agent in cancer. Genes Dis 9:1521\u20131555","journal-title":"Genes Dis"},{"key":"351_CR20","volume":"119","author":"D Lee","year":"2022","unstructured":"Lee D, Goldberg AL (2022) 26S proteasomes become stably activated upon heat shock when ubiquitination and protein degradation increase. Proc Natl Acad Sci USA 119:e2122482119","journal-title":"Proc Natl Acad Sci USA"},{"key":"351_CR21","volume":"7","author":"Y Liu","year":"2021","unstructured":"Liu Y, Sun Y, Han S, Guo Y, Tian Q, Ma Q, Zhang S (2021) CHIP promotes the activation of NF-\u03baB signaling through enhancing the K63-linked ubiquitination of TAK1. Cell Death Discov 7:246","journal-title":"Cell Death Discov"},{"key":"351_CR22","doi-asserted-by":"crossref","first-page":"115190","DOI":"10.1016\/j.biopha.2023.115190","volume":"165","author":"Y Liu","year":"2023","unstructured":"Liu Y, Zhou H, Tang X (2023) STUB1\/CHIP: New insights in cancer and immunity. Biomed Pharmacother 165:115190","journal-title":"Biomed Pharmacother"},{"key":"351_CR23","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.neuint.2017.08.013","volume":"117","author":"BN Lizama","year":"2018","unstructured":"Lizama BN, Palubinsky AM, McLaughlin B (2018) Alterations in the E3 ligases Parkin and CHIP result in unique metabolic signaling defects and mitochondrial quality control issues. Neurochemistry Int 117:139\u2013155","journal-title":"Neurochemistry Int"},{"key":"351_CR24","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.1182\/blood.V114.22.1520.1520","volume":"114","author":"LI Miguel","year":"2009","unstructured":"Miguel LI, Almeida CB, Franco-Penteado CF, Bezerra MAC, Traina F, Dominical VM, Araujo AS, Saad ST, Costa FF, Conran N (2009) Inhibition of phosphodiesterase 9A (PDE9A) significantly reduces cytokine-stimulated adhesion of neutrophils from sickle cell disease individuals, in vitro, but not red cell adhesion. Blood 114:1520","journal-title":"Blood"},{"key":"351_CR25","doi-asserted-by":"crossref","first-page":"e148798","DOI":"10.1172\/JCI148798","volume":"131","author":"S Mishra","year":"2021","unstructured":"Mishra S, Sadagopan N, Dunkerly-Eyring B, Rodriguez S, Sarver DC, Ceddia RP, Murphy SA, Knutsdottir H, Jani VP, Ashok D (2021) Inhibition of phosphodiesterase type 9 reduces obesity and cardiometabolic syndrome in mice. J Clin Investig 131:e148798","journal-title":"J Clin Investig"},{"key":"351_CR26","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.molmed.2017.11.006","volume":"24","author":"N Myeku","year":"2018","unstructured":"Myeku N, Duff KE (2018) Targeting the 26S proteasome to protect against proteotoxic diseases. Trends Mol Med 24:18\u201329","journal-title":"Trends Mol Med"},{"key":"351_CR27","doi-asserted-by":"crossref","first-page":"1692","DOI":"10.1161\/CIRCRESAHA.109.214346","volume":"106","author":"AT Naito","year":"2010","unstructured":"Naito AT, Okada S, Minamino T, Iwanaga K, Liu M-L, Sumida T, Nomura S, Sahara N, Mizoroki T, Takashima A (2010) Promotion of CHIP-mediated p53 degradation protects the heart from ischemic injury. Circ Res 106:1692\u20131702","journal-title":"Circ Res"},{"key":"351_CR28","doi-asserted-by":"crossref","first-page":"2973","DOI":"10.1074\/mcp.M115.051169","volume":"14","author":"V Narayan","year":"2015","unstructured":"Narayan V, Landre V, Ning J, Hernychova L, Muller P, Verma C, Walkinshaw MD, Blackburn EA, Ball KL (2015) Protein\u2013protein interactions modulate the docking-dependent E3-ubiquitin ligase activity of Carboxy-terminus of Hsc70-interacting protein (CHIP). Mol Cell Proteom 14:2973\u20132987","journal-title":"Mol Cell Proteom"},{"key":"351_CR29","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1161\/01.RES.0000256354.95791.f1","volume":"100","author":"K Omori","year":"2007","unstructured":"Omori K, Kotera J (2007) Overview of PDEs and their regulation. Circ Res 100:309\u2013327","journal-title":"Circ Res"},{"key":"351_CR30","doi-asserted-by":"crossref","first-page":"R170","DOI":"10.1016\/j.cub.2018.01.004","volume":"28","author":"S Pickles","year":"2018","unstructured":"Pickles S, Vigi\u00e9 P, Youle RJ (2018) Mitophagy and quality control mechanisms in mitochondrial maintenance. Curr Biol 28:R170\u2013R185","journal-title":"Curr Biol"},{"key":"351_CR31","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-020-18980-x","volume":"11","author":"MJ Ranek","year":"2020","unstructured":"Ranek MJ, Oeing C, Sanchez-Hodge R, Kokkonen-Simon KM, Dillard D, Aslam MI, Rainer PP, Mishra S, Dunkerly-Eyring B, Holewinski RJ (2020) CHIP phosphorylation by protein kinase G enhances protein quality control and attenuates cardiac ischemic injury. Nat Commun 11:5237","journal-title":"Nat Commun"},{"key":"351_CR32","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.tins.2018.02.001","volume":"41","author":"R Ricciarelli","year":"2018","unstructured":"Ricciarelli R, Fedele E (2018) cAMP, cGMP and amyloid \u03b2: three ideal partners for memory formation. Trends Neurosci 41:255\u2013266","journal-title":"Trends Neurosci"},{"key":"351_CR33","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-019-10037-y","volume":"10","author":"L Rinaldi","year":"2019","unstructured":"Rinaldi L, Delle Donne R, Catalanotti B, Torres-Quesada O, Enzler F, Moraca F, Nistic\u00f2 R, Chiuso F, Piccinin S, Bachmann V (2019) Feedback inhibition of cAMP effector signaling by a chaperone-assisted ubiquitin system. Nat Commun 10:2572","journal-title":"Nat Commun"},{"key":"351_CR34","doi-asserted-by":"crossref","first-page":"2080","DOI":"10.7150\/thno.50701","volume":"11","author":"B Rombaut","year":"2021","unstructured":"Rombaut B, Kessels S, Schepers M, Tiane A, Paes D, Solomina Y, Piccart E, van den Hove D, Br\u00f4ne B, Prickaerts J (2021) PDE inhibition in distinct cell types to reclaim the balance of synaptic plasticity. Theranostics 11:2080","journal-title":"Theranostics"},{"key":"351_CR35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/hgv.2014.18","volume":"1","author":"SM Ronnebaum","year":"2014","unstructured":"Ronnebaum SM, Patterson C, Schisler JC (2014) Emerging evidence of coding mutations in the ubiquitin\u2013proteasome system associated with cerebellar ataxias. Hum Genome Var 1:1\u20137","journal-title":"Hum Genome Var"},{"key":"351_CR36","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.neuron.2016.10.001","volume":"92","author":"S Shah","year":"2016","unstructured":"Shah S, Lubeck E, Zhou W, Cai L (2016) In situ transcription profiling of single cells reveals spatial organization of cells in the mouse hippocampus. Neuron 92:342\u2013357","journal-title":"Neuron"},{"key":"351_CR37","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.bbi.2020.05.021","volume":"88","author":"GA Shaw","year":"2020","unstructured":"Shaw GA, Hyer MM, Targett I, Council KR, Dyer SK, Turkson S, Burns CM, Neigh GN (2020) Traumatic stress history interacts with sex and chronic peripheral inflammation to alter mitochondrial function of synaptosomes. Brain, Behav, Immun 88:203\u2013219","journal-title":"Brain, Behav, Immun"},{"key":"351_CR38","doi-asserted-by":"crossref","first-page":"387","DOI":"10.3389\/fneur.2018.00387","volume":"9","author":"C-H Shi","year":"2018","unstructured":"Shi C-H, Cheng Y, Tang M-B, Liu Y-T, Yang Z-H, Li F, Fan Y, Yang J, Xu Y-M (2018a) Analysis of single nucleotide polymorphisms of STK32B, PPARGC1A and CTNNA3 gene with sporadic Parkinson\u2019s disease susceptibility in Chinese Han population. Front Neurol 9:387","journal-title":"Front Neurol"},{"key":"351_CR39","doi-asserted-by":"crossref","first-page":"e1007664","DOI":"10.1371\/journal.pgen.1007664","volume":"14","author":"C-h Shi","year":"2018","unstructured":"Shi C-h, Rubel C, Soss SE, Sanchez-Hodge R, Zhang S, Madrigal SC, Ravi S, McDonough H, Page RC, Chazin WJ (2018b) Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16. PLoS Genet 14:e1007664","journal-title":"PLoS Genet"},{"key":"351_CR40","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1093\/hmg\/ddt497","volume":"23","author":"C-H Shi","year":"2014","unstructured":"Shi C-H, Schisler JC, Rubel CE, Tan S, Song B, McDonough H, Xu L, Portbury AL, Mao C-Y, True C (2014) Ataxia and hypogonadism caused by the loss of ubiquitin ligase activity of the U box protein CHIP. Hum Mol Genet 23:1013\u20131024","journal-title":"Hum Mol Genet"},{"key":"351_CR41","doi-asserted-by":"crossref","first-page":"1543","DOI":"10.1038\/s41564-017-0017-2","volume":"2","author":"KM Sparrer","year":"2017","unstructured":"Sparrer KM, Gableske S, Zurenski MA, Parker ZM, Full F, Baumgart GJ, Kato J, Pacheco-Rodriguez G, Liang C, Pornillos O (2017) TRIM23 mediates virus-induced autophagy via activation of TBK1. Nat Microbiol 2:1543\u20131557","journal-title":"Nat Microbiol"},{"key":"351_CR42","doi-asserted-by":"crossref","first-page":"3353","DOI":"10.1111\/j.1742-4658.2010.07737.x","volume":"277","author":"M Stankiewicz","year":"2010","unstructured":"Stankiewicz M, Nikolay R, Rybin V, Mayer MP (2010) CHIP participates in protein triage decisions by preferentially ubiquitinating Hsp70\u2010bound substrates. FEBS J 277:3353\u20133367","journal-title":"FEBS J"},{"key":"351_CR43","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1146\/annurev-cellbio-100818-125242","volume":"35","author":"AK Stavoe","year":"2019","unstructured":"Stavoe AK, Holzbaur EL (2019) Autophagy in neurons. Annu Rev Cell Dev Biol 35:477\u2013500","journal-title":"Annu Rev Cell Dev Biol"},{"key":"351_CR44","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/S0962-8924(02)02294-8","volume":"12","author":"PJ Stork","year":"2002","unstructured":"Stork PJ, Schmitt JM (2002) Crosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation. Trends Cell Biol 12:258\u2013266","journal-title":"Trends Cell Biol"},{"key":"351_CR45","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1016\/j.tem.2021.04.015","volume":"32","author":"JL Sun-Wang","year":"2021","unstructured":"Sun-Wang JL, Yarritu-Gallego A, Ivanova S, Zorzano A (2021) The ubiquitin-proteasome system and autophagy: self-digestion for metabolic health. Trends Endocrinol Metab 32:594\u2013608","journal-title":"Trends Endocrinol Metab"},{"key":"351_CR46","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1016\/j.neuron.2019.01.049","volume":"101","author":"M Synofzik","year":"2019","unstructured":"Synofzik M, Puccio H, Mochel F, Sch\u00f6ls L (2019) Autosomal recessive cerebellar ataxias: paving the way toward targeted molecular therapies. Neuron 101:560\u2013583","journal-title":"Neuron"},{"key":"351_CR47","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.1080\/15548627.2019.1596477","volume":"15","author":"EN Tsakiri","year":"2019","unstructured":"Tsakiri EN, Gumeni S, Vougas K, Pendin D, Papassideri I, Daga A, Gorgoulis V, Juh\u00e1sz G, Scorrano L, Trougakos IP (2019) Proteasome dysfunction induces excessive proteome instability and loss of mitostasis that can be mitigated by enhancing mitochondrial fusion or autophagy. Autophagy 15:1757\u20131773","journal-title":"Autophagy"},{"key":"351_CR48","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1023\/A:1025704031210","volume":"31","author":"W Van Staveren","year":"2002","unstructured":"Van Staveren W, Glick J, Markerink-van Ittersum M, Shimizu M, Beavo J, Steinbusch H, De Vente J (2002) Cloning and localization of the cGMP-specific phosphodiesterase type 9 in the rat brain. J Neurocytol 31:729\u2013741","journal-title":"J Neurocytol"},{"key":"351_CR49","doi-asserted-by":"crossref","DOI":"10.1038\/srep10210","volume":"5","author":"J Vasco Ferreira","year":"2015","unstructured":"Vasco Ferreira J, Rosa Soares A, Silva Ramalho J, Pereira P, Girao H (2015) K63 linked ubiquitin chain formation is a signal for HIF1A degradation by Chaperone-Mediated Autophagy. Sci Rep 5:10210","journal-title":"Sci Rep"},{"key":"351_CR50","doi-asserted-by":"crossref","first-page":"14220","DOI":"10.1073\/pnas.2003277117","volume":"117","author":"JJ VerPlank","year":"2020","unstructured":"VerPlank JJ, Tyrkalska SD, Fleming A, Rubinsztein DC, Goldberg AL (2020) cGMP via PKG activates 26S proteasomes and enhances degradation of proteins, including ones that cause neurodegenerative diseases. Proc Natl Acad Sci USA 117:14220\u201314230","journal-title":"Proc Natl Acad Sci USA"},{"key":"351_CR51","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1038\/aps.2017.38","volume":"38","author":"P-X Wang","year":"2017","unstructured":"Wang P-X, Li Z-M, Cai S-D, Li J-Y, He P, Huang Y, Feng G-S, Luo H-B, Chen S-R, Liu P-Q (2017) C33 (S), a novel PDE9A inhibitor, protects against rat cardiac hypertrophy through upregulating cGMP signaling. Acta Pharmacol Sin 38:1257\u20131268","journal-title":"Acta Pharmacol Sin"},{"key":"351_CR52","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/j.cell.2022.12.032","volume":"186","author":"DM Wilson","year":"2023","unstructured":"Wilson DM, Cookson MR, Van Den Bosch L, Zetterberg H, Holtzman DM, Dewachter I (2023) Hallmarks of neurodegenerative diseases. Cell 186:693\u2013714","journal-title":"Cell"},{"key":"351_CR53","doi-asserted-by":"crossref","unstructured":"Xiang Y, Naik S, Zhao L, Shi J, Ke H (2024) Emerging phosphodiesterase inhibitors for treatment of neurodegenerative diseases. Med Res Rev 44:1404\u20131445","DOI":"10.1002\/med.22017"},{"key":"351_CR54","doi-asserted-by":"crossref","first-page":"4896","DOI":"10.1523\/JNEUROSCI.3460-13.2014","volume":"34","author":"L Yang","year":"2014","unstructured":"Yang L, Gilbert ML, Zheng R, McKnight GS (2014) Selective expression of a dominant-negative type \u0399\u03b1 PKA regulatory subunit in striatal medium spiny neurons impairs gene expression and leads to reduced feeding and locomotor activity. J Neurosci 34:4896\u20134904","journal-title":"J Neurosci"},{"key":"351_CR55","doi-asserted-by":"crossref","first-page":"1909","DOI":"10.1021\/pr4000043","volume":"12","author":"M-K Yang","year":"2013","unstructured":"Yang M-K, Qiao Z-X, Zhang W-Y, Xiong Q, Zhang J, Li T, Ge F, Zhao J-D (2013) Global phosphoproteomic analysis reveals diverse functions of serine\/threonine\/tyrosine phosphorylation in the model cyanobacterium Synechococcus sp. strain PCC 7002. J Proteome Res 12:1909\u20131923","journal-title":"J Proteome Res"},{"key":"351_CR56","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1161\/CIRCRESAHA.106.144501","volume":"100","author":"M Zaccolo","year":"2007","unstructured":"Zaccolo M, Movsesian MA (2007) cAMP and cGMP signaling cross-talk: role of phosphodiesterases and implications for cardiac pathophysiology. Circ Res 100:1569\u20131578","journal-title":"Circ Res"},{"key":"351_CR57","volume":"18","author":"L Zhang","year":"2021","unstructured":"Zhang L, Dai L, Li D (2021) Mitophagy in neurological disorders. J Neuroinflammation 18:297","journal-title":"J Neuroinflammation"},{"key":"351_CR58","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1007\/s12975-019-00715-w","volume":"11","author":"S Zhang","year":"2020","unstructured":"Zhang S, Hu Z-W, Luo H-Y, Mao C-Y, Tang M-B, Li Y-S, Song B, Wang Y-H, Zhang Z-X, Zhang Q-M (2020a) AAV\/BBB-mediated gene transfer of CHIP attenuates brain injury following experimental intracerebral hemorrhage. Transl Stroke Res 11:296\u2013309","journal-title":"Transl Stroke Res"},{"key":"351_CR59","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1038\/s41419-020-02953-5","volume":"11","author":"S Zhang","year":"2020","unstructured":"Zhang S, Hu Z-W, Mao C-Y, Shi C-H, Xu Y-M (2020b) CHIP as a therapeutic target for neurological diseases. Cell Death Dis 11:727","journal-title":"Cell Death Dis"},{"key":"351_CR60","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1177\/0271678X231208476","volume":"44","author":"Y Zhang","year":"2024","unstructured":"Zhang Y, Jiang M, Gao Y, Zhao W, Wu C, Li C, Li M, Wu D, Wang W, Ji X (2024) \u201cNo-reflow\u201d phenomenon in acute ischemic stroke. J Cereb Blood Flow Metab 44:19\u201337","journal-title":"J Cereb Blood Flow Metab"},{"key":"351_CR61","doi-asserted-by":"crossref","first-page":"115682","DOI":"10.1016\/j.ejmech.2023.115682","volume":"259","author":"L Zheng","year":"2023","unstructured":"Zheng L, Zhou Z-Z (2023) An overview of phosphodiesterase 9 inhibitors: insights from skeletal structure, pharmacophores, and therapeutic potential. Eur J Med Chem 259:115682","journal-title":"Eur J Med Chem"},{"key":"351_CR62","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1002\/JLB.4RU0620-397RR","volume":"111","author":"Q Zhou","year":"2022","unstructured":"Zhou Q, Zhang J (2022) K27-linked noncanonic ubiquitination in immune regulation. J Leukoc Biol 111:223\u2013235","journal-title":"J Leukoc Biol"}],"container-title":["The EMBO Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1038\/s44318-024-00351-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1038\/s44318-024-00351-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1038\/s44318-024-00351-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:41:04Z","timestamp":1779237664000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1038\/s44318-024-00351-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,13]]},"references-count":62,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,2,17]]}},"alternative-id":["351"],"URL":"https:\/\/doi.org\/10.1038\/s44318-024-00351-7","relation":{},"ISSN":["1460-2075"],"issn-type":[{"value":"1460-2075","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,13]]},"assertion":[{"value":"30 January 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 December 2024","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 December 2024","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 January 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Disclosure and competing interests statement"}}]}}