{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T15:59:39Z","timestamp":1791820779498,"version":"4.3.4"},"reference-count":55,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,3,24]],"date-time":"2023-03-24T00:00:00Z","timestamp":1679616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science and Technology Council","award":["NSTC-109-2314-B-195-015-MY3"],"award-info":[{"award-number":["NSTC-109-2314-B-195-015-MY3"]}]},{"name":"National Science and Technology Council","award":["NSTC-109-2314-B-195-014-MY2"],"award-info":[{"award-number":["NSTC-109-2314-B-195-014-MY2"]}]},{"name":"National Science and Technology Council","award":["MMH-E-110-02"],"award-info":[{"award-number":["MMH-E-110-02"]}]},{"name":"National Science and Technology Council","award":["MMH-E-111-02"],"award-info":[{"award-number":["MMH-E-111-02"]}]},{"name":"MacKay Memorial Hospital","award":["NSTC-109-2314-B-195-015-MY3"],"award-info":[{"award-number":["NSTC-109-2314-B-195-015-MY3"]}]},{"name":"MacKay Memorial Hospital","award":["NSTC-109-2314-B-195-014-MY2"],"award-info":[{"award-number":["NSTC-109-2314-B-195-014-MY2"]}]},{"name":"MacKay Memorial Hospital","award":["MMH-E-110-02"],"award-info":[{"award-number":["MMH-E-110-02"]}]},{"name":"MacKay Memorial Hospital","award":["MMH-E-111-02"],"award-info":[{"award-number":["MMH-E-111-02"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>We have shown in vivo and in vitro previously that psychosine causes dysfunction of autophagy and the ubiquitin-proteasome system underlying the pathogenesis of globoid cell leukodystrophy (GLD), a devastating lysosomal storage disease complicated by global demyelination. Here, we investigated the therapeutic efficacy of the mTOR inhibitor rapamycin in twitcher mice, a murine model of infantile GLD, in biochemical, histochemical, and clinical aspects. Administration of rapamycin to twitcher mice inhibited mTOR signaling in the brains, and significantly reduced the accumulation of insoluble ubiquitinated protein and the formation of ubiquitin aggregates. The astrocytes and microglia reactivity were attenuated in that reactive astrocytes, ameboid microglia, and globoid cells were reduced in the brains of rapamycin-treated twitcher mice. Furthermore, rapamycin improved the cortical myelination, neurite density, and rescued the network complexity in the cortex of twitcher mice. The therapeutic action of rapamycin on the pathology of the twitcher mice\u2019s brains prolonged the longevity of treated twitcher mice. Overall, these findings validate the therapeutic efficacy of rapamycin and highlight enhancing degradation of aggregates as a therapeutic strategy to modulate neuroinflammation, demyelination, and disease progression of GLD and other leukodystrophies associated with intracellular aggregates.<\/jats:p>","DOI":"10.3390\/cells12070993","type":"journal-article","created":{"date-parts":[[2023,3,24]],"date-time":"2023-03-24T04:31:05Z","timestamp":1679632265000},"page":"993","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Rapamycin Alleviates Protein Aggregates, Reduces Neuroinflammation, and Rescues Demyelination in Globoid Cell Leukodystrophy"],"prefix":"10.3390","volume":"12","author":[{"given":"Dar-Shong","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Pediatrics, MacKay Memorial Hospital, Taipei 10449, Taiwan"},{"name":"Department of Medicine, MacKay Medical College, New Taipei 25245, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Wen","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Medical Research, MacKay Memorial Hospital, Taipei 10449, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsung-Han","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Medical Research, MacKay Memorial Hospital, Taipei 10449, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lung","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, MacKay Memorial Hospital, Taipei 10449, Taiwan"},{"name":"Department of Medicine, MacKay Medical College, New Taipei 25245, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zon-Darr","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Medical Research, MacKay Memorial Hospital, Taipei 10449, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsu-Yen","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Medical Research, MacKay Memorial Hospital, Taipei 10449, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuan-Jen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, MacKay Memorial Hospital, Taipei 10449, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Che-Sheng","family":"Ho","sequence":"additional","affiliation":[{"name":"Department of Medicine, MacKay Medical College, New Taipei 25245, Taiwan"},{"name":"Department of Neurology, MacKay Children\u2019s Hospital, Taipei 10449, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1002\/jnr.23743","article-title":"Krabbe disease: One Hundred years from the bedside to the bench to the bedside","volume":"94","author":"Wenger","year":"2016","journal-title":"J. Neurosci. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.pediatrneurol.2008.08.011","article-title":"The Hunter\u2019s Hope Krabbe family database","volume":"40","author":"Duffner","year":"2009","journal-title":"Pediatr. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1073\/pnas.66.2.302","article-title":"Globoid cell leucodystrophy (Krabbe\u2019s disease): Deficiency of galactocerebroside beta-galactosidase","volume":"66","author":"Suzuki","year":"1970","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1002\/(SICI)1098-1004(1997)10:4<268::AID-HUMU2>3.0.CO;2-D","article-title":"Molecular genetics of Krabbe disease (globoid cell leukodystrophy): Diagnostic and clinical implications","volume":"10","author":"Wenger","year":"1997","journal-title":"Hum. Mutat."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/978-1-4684-7735-1_8","article-title":"Chemical Pathology of Krabbe Disease: The Occurrence of Psychosine and Other Neutral Sphingoglycolipids","volume":"68","author":"Vanier","year":"1976","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/S0022-2275(20)39839-4","article-title":"Krabbe disease: A galactosylsphingosine (psychosine) lipidosis","volume":"21","author":"Svennerholm","year":"1980","journal-title":"J. Lipid Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1016\/0006-291X(72)90381-6","article-title":"Globoid cell leukodystrophy: Additional deficiency of psychosine galactosidase","volume":"48","author":"Miyatake","year":"1972","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1111\/j.1750-3639.1995.tb00601.x","article-title":"The twitcher mouse: A model for Krabbe disease and for experimental therapies","volume":"5","author":"Suzuki","year":"1995","journal-title":"Brain Pathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5398","DOI":"10.1016\/S0021-9258(20)81118-1","article-title":"Galactosylsphingosine galactosyl hydrolase. Partial purification and properties of the enzyme in rat brain","volume":"247","author":"Miyatake","year":"1972","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"20097","DOI":"10.1073\/pnas.1912108116","article-title":"Genetic ablation of acid ceramidase in Krabbe disease confirms the psychosine hypothesis and identifies a new therapeutic target","volume":"116","author":"Li","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.nbd.2018.08.023","article-title":"Developmental defects and aberrant accumulation of endogenous psychosine in oligodendrocytes in a murine model of Krabbe disease","volume":"120","author":"Inamura","year":"2018","journal-title":"Neurobiol. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"10048","DOI":"10.1523\/JNEUROSCI.0217-13.2013","article-title":"The sphingolipid psychosine inhibits fast axonal transport in Krabbe disease by activation of GSK3beta and deregulation of molecular motors","volume":"33","author":"Givogri","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/S1357-4310(00)01800-1","article-title":"Murine, canine and non-human primate models of Krabbe disease","volume":"6","author":"Wenger","year":"2000","journal-title":"Mol. Med. Today"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Lin, D.-S., Ho, C.-S., Huang, Y.-W., Wu, T.-Y., Lee, T.-H., Huang, Z.-D., Wang, T.-J., Yang, S.-J., and Chiang, M.-F. (2020). Impairment of Proteasome and Autophagy Underlying the Pathogenesis of Leukodystrophy. Cells, 9.","DOI":"10.3390\/cells9051124"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/15548627.2020.1797280","article-title":"Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)","volume":"17","author":"Klionsky","year":"2021","journal-title":"Autophagy"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.nbd.2019.05.011","article-title":"Dysregulated autophagy as a new aspect of the molecular pathogenesis of Krabbe disease","volume":"129","author":"Angella","year":"2019","journal-title":"Neurobiol. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.ymgme.2013.09.011","article-title":"Characterization and application of a disease-cell model for a neurodegenerative lysosomal disease","volume":"111","author":"Ribbens","year":"2014","journal-title":"Mol. Genet. Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1002\/jnr.23910","article-title":"Lithium improves cell viability in psychosine-treated MO3.13 human oligodendrocyte cell line via autophagy activation","volume":"94","author":"Antonini","year":"2016","journal-title":"J. Neurosci. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1074\/mcp.RA118.001267","article-title":"Quantitative Microproteomics Based Characterization of the Central and Peripheral Nervous System of a Mouse Model of Krabbe Disease","volume":"18","author":"Pellegrini","year":"2019","journal-title":"Mol. Cell. Proteom."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1172\/JCI73939","article-title":"mTOR: A pharmacologic target for autophagy regulation","volume":"125","author":"Kim","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"15790","DOI":"10.1073\/pnas.1521919112","article-title":"mTOR inhibition activates overall protein degradation by the ubiquitin proteasome system as well as by autophagy","volume":"112","author":"Zhao","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.cmet.2014.01.001","article-title":"Rapamycin: One drug, many effects","volume":"19","author":"Li","year":"2014","journal-title":"Cell Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1038\/ng1362","article-title":"Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease","volume":"36","author":"Ravikumar","year":"2004","journal-title":"Nat. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1093\/hmg\/ddi458","article-title":"Rapamycin alleviates toxicity of different aggregate-prone proteins","volume":"15","author":"Berger","year":"2006","journal-title":"Hum. Mol. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1038\/nature05853","article-title":"HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS","volume":"447","author":"Pandey","year":"2007","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1046\/j.1471-4159.1996.66031118.x","article-title":"Molecular Cloning and Expression of cDNA for Murine Galactocerebrosidase and Mutation Analysis of the Twitcher Mouse, a Model of Krabbe\u2019s Disease","volume":"66","author":"Sakai","year":"1996","journal-title":"J. Neurochem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1002\/jnr.23773","article-title":"A microglial hypothesis of globoid cell leukodystrophy pathology","volume":"94","author":"Nicaise","year":"2016","journal-title":"J. Neurosci. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1016\/j.ajpath.2013.10.011","article-title":"Innate Immune Activation in the Pathogenesis of a Murine Model of Globoid Cell Leukodystrophy","volume":"184","author":"Snook","year":"2014","journal-title":"Am. J. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"16492","DOI":"10.1038\/s41598-017-16797-1","article-title":"A quantitative method for microstructural analysis of myelinated axons in the injured rodent brain","volume":"7","author":"Dijkhuizen","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5356","DOI":"10.1038\/s41467-020-19179-w","article-title":"Brainstem development requires galactosylceramidase and is critical for pathogenesis in a model of Krabbe disease","volume":"11","author":"Weinstock","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_31","first-page":"227","article-title":"Expression of glial fibrillary acidic protein in the CNS and PNS of murine globoid cell leukodystrophy, the twitcher","volume":"125","author":"Kobayashi","year":"1986","journal-title":"Am. J. Pathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1002\/jnr.23804","article-title":"Neuroimmune mechanisms in Krabbe\u2019s disease","volume":"94","author":"Potter","year":"2016","journal-title":"J. Neurosci. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1002\/path.5576","article-title":"Autophagy in white matter disorders of the CNS : Mechanisms and therapeutic opportunities","volume":"253","author":"Nutma","year":"2021","journal-title":"J. Pathol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Folts, C.J., Scott-Hewitt, N., Pr\u00f6schel, C., Mayer-Pr\u00f6schel, M., and Noble, M. (2016). Lysosomal Re-acidification Prevents Lysosphingolipid-Induced Lysosomal Impairment and Cellular Toxicity. PLoS Biol., 14.","DOI":"10.1371\/journal.pbio.1002583"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1038\/nature18943","article-title":"An evolutionarily conserved pathway controls proteasome homeostasis","volume":"536","author":"Rousseau","year":"2016","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"120137","DOI":"10.1098\/rsob.120137","article-title":"Synergistic effects of TOR and proteasome pathways on the yeast transcriptome and cell growth","volume":"3","author":"Zhang","year":"2013","journal-title":"Open Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1128\/MMBR.66.4.579-591.2002","article-title":"Elucidating TOR Signaling and Rapamycin Action: Lessons from Saccharomyces cerevisiae","volume":"66","author":"Crespo","year":"2002","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Majumder, S., Richardson, A., Strong, R., and Oddo, S. (2011). Inducing Autophagy by Rapamycin Before, but Not After, the Formation of Plaques and Tangles Ameliorates Cognitive Deficits. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0025416"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"642900","DOI":"10.3389\/fphar.2021.642900","article-title":"Corynoxine Protects Dopaminergic Neurons Through Inducing Autophagy and Diminishing Neuroinflammation in Rotenone-Induced Animal Models of Parkinson\u2019s Disease","volume":"12","author":"Chen","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.ebiom.2019.10.036","article-title":"Small molecule modulator of aggrephagy regulates neuroinflammation to curb pathogenesis of neurodegeneration","volume":"50","author":"Sn","year":"2019","journal-title":"Ebiomedicine"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Siman, R., Cocca, R., and Dong, Y. (2015). The mTOR Inhibitor Rapamycin Mitigates Perforant Pathway Neurodegeneration and Synapse Loss in a Mouse Model of Early-Stage Alzheimer-Type Tauopathy. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0142340"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.mcn.2015.04.006","article-title":"Rapamycin increases neuronal survival, reduces inflammation and astrocyte proliferation after spinal cord injury","volume":"68","author":"Goldshmit","year":"2015","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e2611","DOI":"10.1038\/cddis.2016.491","article-title":"Rapamycin upregulates glutamate transporter and IL-6 expression in astrocytes in a mouse model of Parkinson\u2019s disease","volume":"8","author":"Zhang","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1007\/PL00007400","article-title":"NACP\/\u03b1-synuclein-positive filamentous inclusions in astrocytes and oligodendrocytes of Parkinson\u2019s disease brains","volume":"99","author":"Wakabayashi","year":"2000","journal-title":"Acta Neuropathol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1002\/ana.21465","article-title":"Multiple system atrophy: A primary oligodendrogliopathy","volume":"64","author":"Wenning","year":"2008","journal-title":"Ann. Neurol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"11388","DOI":"10.1523\/JNEUROSCI.1356-10.2010","article-title":"Rapamycin Activates Autophagy and Improves Myelination in Explant Cultures from Neuropathic Mice","volume":"30","author":"Rangaraju","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"10672","DOI":"10.1523\/JNEUROSCI.23-33-10672.2003","article-title":"Emerging Role for Autophagy in the Removal of Aggresomes in Schwann Cells","volume":"23","author":"Fortun","year":"2003","journal-title":"J. Neurosci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.nbd.2006.09.018","article-title":"The formation of peripheral myelin protein 22 aggregates is hindered by the enhancement of autophagy and expression of cytoplasmic chaperones","volume":"25","author":"Fortun","year":"2007","journal-title":"Neurobiol. Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.nbd.2011.08.024","article-title":"Neuronal and glia abnormalities in Tsc1-deficient forebrain and partial rescue by rapamycin","volume":"45","author":"Carson","year":"2012","journal-title":"Neurobiol. Dis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"201","DOI":"10.3389\/fncel.2018.00201","article-title":"mTORC1 Activation by Loss of Tsc1 in Myelinating Glia Causes Downregulation of Quaking and Neurofascin 155 Leading to Paranodal Domain Disorganization","volume":"12","author":"Shi","year":"2018","journal-title":"Front. Cell. Neurosci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"590884","DOI":"10.3389\/fneur.2020.590884","article-title":"Rapamycin Alleviates the Symptoms of Multiple Sclerosis in Experimental Autoimmune Encephalomyelitis (EAE) Through Mediating the TAM-TLRs-SOCS Pathway","volume":"11","author":"Li","year":"2020","journal-title":"Front. Neurol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"574041","DOI":"10.3389\/fnmol.2020.574041","article-title":"Rapamycin Preserves Neural Tissue, Promotes Schwann Cell Myelination and Reduces Glial Scar Formation After Hemi-Contusion Spinal Cord Injury in Mice","volume":"13","author":"Liu","year":"2020","journal-title":"Front. Mol. Neurosci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1002\/(SICI)1097-4547(20000415)60:2<231::AID-JNR12>3.0.CO;2-E","article-title":"L-cycloserine slows the clinical and pathological course in mice with globoid cell leukodystrophy (twitcher mice)","volume":"60","author":"LeVine","year":"2000","journal-title":"J. Neurosci. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.ymgme.2011.05.005","article-title":"CNS-targeted AAV5 gene transfer results in global dispersal of vector and prevention of morphological and function deterioration in CNS of globoid cell leukodystrophy mouse model","volume":"103","author":"Lin","year":"2011","journal-title":"Mol. Genet. Metab."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"6495","DOI":"10.1523\/JNEUROSCI.4199-14.2015","article-title":"Mechanism-Based Combination Treatment Dramatically Increases Therapeutic Efficacy in Murine Globoid Cell Leukodystrophy","volume":"35","author":"Shea","year":"2015","journal-title":"J. Neurosci."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/7\/993\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:02:06Z","timestamp":1760122926000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/7\/993"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,24]]},"references-count":55,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["cells12070993"],"URL":"https:\/\/doi.org\/10.3390\/cells12070993","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,24]]}}}