{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"Research Square"}],"indexed":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T06:38:47Z","timestamp":1747204727082,"version":"3.40.5"},"posted":{"date-parts":[[2023,6,12]]},"group-title":"In Review","reference-count":89,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2023,6,12]],"date-time":"2023-06-12T00:00:00Z","timestamp":1686528000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,6,7]]},"abstract":"<title>Abstract<\/title>\n        <p>Unbiased phenotypic screens in patient-relevant disease models offer the potential to detect novel therapeutic targets for rare diseases. In this study, we developed a high-throughput screening assay to identify molecules that correct aberrant protein trafficking in adaptor protein complex 4 (AP-4) deficiency, a rare but prototypical form of childhood-onset hereditary spastic paraplegia, characterized by mislocalization of the autophagy protein ATG9A. Using high-content microscopy and an automated image analysis pipeline, we screened a diversity library of 28,864 small molecules and identified a lead compound, <italic>C-01<\/italic>, that restored ATG9A pathology in multiple disease models, including patient-derived fibroblasts and induced pluripotent stem cell-derived neurons. We used multiparametric orthogonal strategies and integrated transcriptomic and proteomic approaches to delineate putative molecular targets of <italic>C-01<\/italic> and potential mechanisms of action. Our results define molecular regulators of intracellular ATG9A trafficking and characterize a lead compound for the treatment of AP-4 deficiency, providing important proof-of-concept data for future Investigational New Drug (IND)-enabling studies.<\/p>","DOI":"10.21203\/rs.3.rs-3036166\/v1","type":"posted-content","created":{"date-parts":[[2023,6,12]],"date-time":"2023-06-12T19:04:48Z","timestamp":1686596688000},"source":"Crossref","is-referenced-by-count":1,"title":["High-Content Small Molecule Screen Identifies a Novel Compound That Restores AP-4-Dependent Protein Trafficking in Neuronal Models of AP-4-Associated Hereditary Spastic Paraplegia"],"prefix":"10.21203","author":[{"given":"Afshin","family":"Saffari","sequence":"first","affiliation":[{"name":"Boston Children's Hospital, Harvard Medical School"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara","family":"Brechmann","sequence":"additional","affiliation":[{"name":"Boston Children's Hospital, Harvard Medical School"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cedric","family":"Boeger","sequence":"additional","affiliation":[{"name":"Boston Children's Hospital, Harvard Medical School"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9488-7893","authenticated-orcid":false,"given":"Wardiya Afshar","family":"Saber","sequence":"additional","affiliation":[{"name":"Boston Children's Hospital\/Harvard Medical School"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0495-5317","authenticated-orcid":false,"given":"Hellen","family":"jumo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6895-9627","authenticated-orcid":false,"given":"Dosh","family":"Whye","sequence":"additional","affiliation":[{"name":"Boston Children's Hospital, Harvard Medical School"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Delaney","family":"Wood","sequence":"additional","affiliation":[{"name":"Boston Children's Hospital, Harvard Medical School"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lara","family":"Wahlster","sequence":"additional","affiliation":[{"name":"Boston Children's Hospital, Harvard Medical School"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julian","family":"Alecu","sequence":"additional","affiliation":[{"name":"Boston Children's Hospital, Harvard Medical School"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0504-7815","authenticated-orcid":false,"given":"Marvin","family":"Ziegler","sequence":"additional","affiliation":[{"name":"Harvard Medical School"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marlene","family":"Scheffold","sequence":"additional","affiliation":[{"name":"Boston Children's Hospital, Harvard Medical School"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kellen","family":"Winden","sequence":"additional","affiliation":[{"name":"Boston Children's Hospital"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jed","family":"Hubbs","sequence":"additional","affiliation":[{"name":"Boston Children's Hospital"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3194-5413","authenticated-orcid":false,"given":"Elizabeth","family":"Buttermore","sequence":"additional","affiliation":[{"name":"Boston Children's Hospital"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lee","family":"Barrett","sequence":"additional","affiliation":[{"name":"Boston Children's Hospital"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3166-3435","authenticated-orcid":false,"given":"Georg","family":"Borner","sequence":"additional","affiliation":[{"name":"Max Planck Institute of Biochemistry"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1594-8780","authenticated-orcid":false,"given":"Alexandra","family":"Davies","sequence":"additional","affiliation":[{"name":"Max Planck Institute of Biochemistry"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7044-2953","authenticated-orcid":false,"given":"Mustafa","family":"Sahin","sequence":"additional","affiliation":[{"name":"Boston Children's Hospital"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0026-4714","authenticated-orcid":false,"given":"Darius","family":"Ebrahimi-Fakhari","sequence":"additional","affiliation":[{"name":"Boston Children's Hospital, Harvard Medical School"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1038\/s41573-019-0049-9","article-title":"Therapies for rare diseases: therapeutic modalities, progress and challenges ahead","volume":"19","author":"Tambuyzer E,","year":"2020","unstructured":"Tambuyzer E, et al. Therapies for rare diseases: therapeutic modalities, progress and challenges ahead. Nat Rev Drug Discov 19, 93\u2013111 (2020).","journal-title":"Nat Rev Drug Discov"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1038\/nrd.2017.111","article-title":"Opportunities and challenges in phenotypic drug discovery: an industry perspective","volume":"16","author":"Moffat JG","year":"2017","unstructured":"Moffat JG, Vincent F, Lee JA, Eder J, Prunotto M. Opportunities and challenges in phenotypic drug discovery: an industry perspective. Nat Rev Drug Discov 16, 531\u2013543 (2017).","journal-title":"Nat Rev Drug Discov"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/nrd4336","article-title":"The discovery of first-in-class drugs: origins and evolution","volume":"13","author":"Eder J","year":"2014","unstructured":"Eder J, Sedrani R, Wiesmann C. The discovery of first-in-class drugs: origins and evolution. Nat Rev Drug Discov 13, 577\u2013587 (2014).","journal-title":"Nat Rev Drug Discov"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.1002\/ajmg.a.38326","article-title":"Drug discovery and development for rare genetic disorders","volume":"173","author":"Sun W","year":"2017","unstructured":"Sun W, Zheng W, Simeonov A. Drug discovery and development for rare genetic disorders. Am J Med Genet A 173, 2307\u20132322 (2017).","journal-title":"Am J Med Genet A"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1038\/nrd3368","article-title":"Impact of high-throughput screening in biomedical research","volume":"10","author":"Macarron R,","year":"2011","unstructured":"Macarron R, et al. Impact of high-throughput screening in biomedical research. Nat Rev Drug Discov 10, 188\u2013195 (2011).","journal-title":"Nat Rev Drug Discov"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"293ps215","DOI":"10.1126\/scitranslmed.aab1201","article-title":"Developing predictive assays: the phenotypic screening \"rule of 3\"","volume":"7","author":"Vincent F,","year":"2015","unstructured":"Vincent F, et al. Developing predictive assays: the phenotypic screening \"rule of 3\". Sci Transl Med 7, 293ps215 (2015).","journal-title":"Sci Transl Med"},{"year":"2018","author":"Ebrahimi-Fakhari D","key":"ref7","unstructured":"Ebrahimi-Fakhari D, Behne R, Davies AK, Hirst J. AP-4-Associated Hereditary Spastic Paraplegia. In: GeneReviews((R)) (eds Adam MP, et al.) (2018)."},{"key":"ref8","first-page":"2929","article-title":"Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia","volume":"143","author":"Ebrahimi-Fakhari D,","year":"2020","unstructured":"Ebrahimi-Fakhari D, et al. Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia. Brain 143, 2929\u20132944 (2020).","journal-title":"Brain"},{"key":"ref9","article-title":"Systematic Analysis of Brain MRI Findings in Adaptor Protein Complex 4-Associated Hereditary Spastic Paraplegia","volume":"97","author":"Ebrahimi-Fakhari D,","unstructured":"Ebrahimi-Fakhari D, et al. Systematic Analysis of Brain MRI Findings in Adaptor Protein Complex 4-Associated Hereditary Spastic Paraplegia. Neurology 97, e1942-e1954 (2021).","journal-title":"Neurology"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1002\/ajmg.a.38561","article-title":"Clinical and genetic characterization of AP4B1-associated SPG47","volume":"176","author":"Ebrahimi-Fakhari D,","year":"2018","unstructured":"Ebrahimi-Fakhari D, et al. Clinical and genetic characterization of AP4B1-associated SPG47. Am J Med Genet A 176, 311\u2013318 (2018).","journal-title":"Am J Med Genet A"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"E10697-E10706","DOI":"10.1073\/pnas.1717327114","article-title":"AP-4 mediates export of ATG9A from the trans-Golgi network to promote autophagosome formation","volume":"114","author":"Mattera R","year":"2017","unstructured":"Mattera R, Park SY, De Pace R, Guardia CM, Bonifacino JS. AP-4 mediates export of ATG9A from the trans-Golgi network to promote autophagosome formation. Proc Natl Acad Sci U S A 114, E10697-E10706 (2017).","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"3958","DOI":"10.1038\/s41467-018-06172-7","article-title":"AP-4 vesicles contribute to spatial control of autophagy via RUSC-dependent peripheral delivery of ATG9A","volume":"9","author":"Davies AK,","year":"2018","unstructured":"Davies AK, et al. AP-4 vesicles contribute to spatial control of autophagy via RUSC-dependent peripheral delivery of ATG9A. Nat Commun 9, 3958 (2018).","journal-title":"Nat Commun"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"e1007363","DOI":"10.1371\/journal.pgen.1007363","article-title":"Altered distribution of ATG9A and accumulation of axonal aggregates in neurons from a mouse model of AP-4 deficiency syndrome","volume":"14","author":"Pace R","year":"2018","unstructured":"De Pace R, et al. Altered distribution of ATG9A and accumulation of axonal aggregates in neurons from a mouse model of AP-4 deficiency syndrome. PLoS Genet 14, e1007363 (2018).","journal-title":"PLoS Genet"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1080\/15548627.2019.1615302","article-title":"Axonal autophagosome maturation defect through failure of ATG9A sorting underpins pathology in AP-4 deficiency syndrome","volume":"16","author":"Ivankovic D,","year":"2020","unstructured":"Ivankovic D, et al. Axonal autophagosome maturation defect through failure of ATG9A sorting underpins pathology in AP-4 deficiency syndrome. Autophagy 16, 391\u2013407 (2020).","journal-title":"Autophagy"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1093\/hmg\/ddz310","article-title":"Adaptor protein complex 4 deficiency: a paradigm of childhood-onset hereditary spastic paraplegia caused by defective protein trafficking","volume":"29","author":"Behne R,","year":"2020","unstructured":"Behne R, et al. Adaptor protein complex 4 deficiency: a paradigm of childhood-onset hereditary spastic paraplegia caused by defective protein trafficking. Hum Mol Genet 29, 320\u2013334 (2020).","journal-title":"Hum Mol Genet"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"7278","DOI":"10.1074\/jbc.274.11.7278","article-title":"AP-4, a novel protein complex related to clathrin adaptors","volume":"274","author":"Dell'Angelica EC","year":"1999","unstructured":"Dell'Angelica EC, Mullins C, Bonifacino JS. AP-4, a novel protein complex related to clathrin adaptors. J Biol Chem 274, 7278\u20137285 (1999).","journal-title":"J Biol Chem"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"2787","DOI":"10.1091\/mbc.10.8.2787","article-title":"Characterization of a fourth adaptor-related protein complex","volume":"10","author":"Hirst J","year":"1999","unstructured":"Hirst J, Bright NA, Rous B, Robinson MS. Characterization of a fourth adaptor-related protein complex. Mol Biol Cell 10, 2787\u20132802 (1999).","journal-title":"Mol Biol Cell"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1002\/pro.3870","article-title":"Integrating structural and evolutionary data to interpret variation and pathogenicity in adapter protein complex 4","volume":"29","author":"Gadbery JE,","year":"2020","unstructured":"Gadbery JE, et al. Integrating structural and evolutionary data to interpret variation and pathogenicity in adapter protein complex 4. Protein Sci 29, 1535\u20131549 (2020).","journal-title":"Protein Sci"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"jcs222992","DOI":"10.1242\/jcs.222992","article-title":"Adaptor protein complexes and disease at a glance","volume":"132","author":"Sanger A","year":"2019","unstructured":"Sanger A, Hirst J, Davies AK, Robinson MS. Adaptor protein complexes and disease at a glance. J Cell Sci 132, jcs222992 (2019).","journal-title":"J Cell Sci"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1146\/annurev-cellbio-100818-125234","article-title":"Genetic Disorders of Protein Coats","volume":"35","author":"Dell'Angelica EC","year":"2019","unstructured":"Dell'Angelica EC, Bonifacino JS. Coatopathies: Genetic Disorders of Protein Coats. Annu Rev Cell Dev Biol 35, 131\u2013168 (2019).","journal-title":"Annu Rev Cell Dev Biol"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"fcab221","DOI":"10.1093\/braincomms\/fcab221","article-title":"High-throughput imaging of ATG9A distribution as a diagnostic functional assay for adaptor protein complex 4-associated hereditary spastic paraplegia","volume":"3","author":"Ebrahimi-Fakhari D","year":"2021","unstructured":"Ebrahimi-Fakhari D, et al. High-throughput imaging of ATG9A distribution as a diagnostic functional assay for adaptor protein complex 4-associated hereditary spastic paraplegia. Brain Commun 3, fcab221 (2021).","journal-title":"Brain Commun"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1093\/brain\/awv371","article-title":"Congenital disorders of autophagy: an emerging novel class of inborn errors of neuro-metabolism","volume":"139","author":"Ebrahimi-Fakhari D,","year":"2016","unstructured":"Ebrahimi-Fakhari D, et al. Congenital disorders of autophagy: an emerging novel class of inborn errors of neuro-metabolism. Brain 139, 317\u2013337 (2016).","journal-title":"Brain"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1002\/jimd.12084","article-title":"Novel insights into the clinical and molecular spectrum of congenital disorders of autophagy","volume":"43","author":"Teinert J","year":"2020","unstructured":"Teinert J, Behne R, Wimmer M, Ebrahimi-Fakhari D. Novel insights into the clinical and molecular spectrum of congenital disorders of autophagy. J Inherit Metab Dis 43, 51\u201362 (2020).","journal-title":"J Inherit Metab Dis"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1002\/acn3.51018","article-title":"Loss of ap4s1 in zebrafish leads to neurodevelopmental defects resembling spastic paraplegia 52","volume":"7","author":"D'Amore A,","year":"2020","unstructured":"D'Amore A, et al. Loss of ap4s1 in zebrafish leads to neurodevelopmental defects resembling spastic paraplegia 52. Ann Clin Transl Neurol 7, 584\u2013589 (2020).","journal-title":"Ann Clin Transl Neurol"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"e544","DOI":"10.1212\/NXG.0000000000000544","article-title":"Blended Phenotype of Silver-Russell Syndrome and SPG50 Caused by Maternal Isodisomy of Chromosome 7","volume":"7","author":"Ziegler M,","year":"2021","unstructured":"Ziegler M, et al. Blended Phenotype of Silver-Russell Syndrome and SPG50 Caused by Maternal Isodisomy of Chromosome 7. Neurol Genet 7, e544 (2021).","journal-title":"Neurol Genet"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1016\/j.neuron.2008.02.012","article-title":"Accumulation of AMPA receptors in autophagosomes in neuronal axons lacking adaptor protein AP-4","volume":"57","author":"Matsuda S,","year":"2008","unstructured":"Matsuda S, et al. Accumulation of AMPA receptors in autophagosomes in neuronal axons lacking adaptor protein AP-4. Neuron 57, 730\u2013745 (2008).","journal-title":"Neuron"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"fcac335","DOI":"10.1093\/braincomms\/fcac335","article-title":"Ap4b1-knockout mouse model of hereditary spastic paraplegia type 47 displays motor dysfunction, aberrant brain morphology and ATG9A mislocalization","volume":"5","author":"Scarrott JM,","year":"2023","unstructured":"Scarrott JM, et al. Ap4b1-knockout mouse model of hereditary spastic paraplegia type 47 displays motor dysfunction, aberrant brain morphology and ATG9A mislocalization. Brain Commun 5, fcac335 (2023).","journal-title":"Brain Commun"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1080\/15548627.2017.1314897","article-title":"Atg9a deficiency causes axon-specific lesions including neuronal circuit dysgenesis","volume":"14","author":"Yamaguchi J,","year":"2018","unstructured":"Yamaguchi J, et al. Atg9a deficiency causes axon-specific lesions including neuronal circuit dysgenesis. Autophagy 14, 764\u2013777 (2018).","journal-title":"Autophagy"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1038\/s41467-022-28609-w","article-title":"AP-4-mediated axonal transport controls endocannabinoid production in neurons","volume":"13","author":"Davies AK,","year":"2022","unstructured":"Davies AK, et al. AP-4-mediated axonal transport controls endocannabinoid production in neurons. Nat Commun 13, 1058 (2022).","journal-title":"Nat Commun"},{"year":"2004","author":"Bray MA","key":"ref30","unstructured":"Bray MA, Carpenter A. Advanced Assay Development Guidelines for Image-Based High Content Screening and Analysis, 2004 edn. Eli Lilly & Company and the National Center for Advancing Translational Sciences (2017)."},{"key":"ref31","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1177\/1087057111405851","article-title":"Illustration of SSMD, z score, SSMD*, z* score, and t statistic for hit selection in RNAi high-throughput screens","volume":"16","author":"Zhang XD","year":"2011","unstructured":"Zhang XD. Illustration of SSMD, z score, SSMD*, z* score, and t statistic for hit selection in RNAi high-throughput screens. J Biomol Screen 16, 775\u2013785 (2011).","journal-title":"J Biomol Screen"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/nbt1186","article-title":"Statistical practice in high-throughput screening data analysis","volume":"24","author":"Malo N","year":"2006","unstructured":"Malo N, Hanley JA, Cerquozzi S, Pelletier J, Nadon R. Statistical practice in high-throughput screening data analysis. Nat Biotechnol 24, 167\u2013175 (2006).","journal-title":"Nat Biotechnol"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/978-1-62703-640-5_2","article-title":"Considerations for the use of SH-SY5Y neuroblastoma cells in neurobiology","volume":"1078","author":"Kovalevich J","year":"2013","unstructured":"Kovalevich J, Langford D. Considerations for the use of SH-SY5Y neuroblastoma cells in neurobiology. Methods Mol Biol 1078, 9\u201321 (2013).","journal-title":"Methods Mol Biol"},{"year":"2017","author":"Rohban MH,","key":"ref34","unstructured":"Rohban MH, et al. Systematic morphological profiling of human gene and allele function via Cell Painting. Elife 6, (2017)."},{"key":"ref35","doi-asserted-by":"crossref","first-page":"102335","DOI":"10.1016\/j.scr.2021.102335","article-title":"Generation and characterization of six human induced pluripotent stem cell lines (iPSC) from three families with AP4M1-associated hereditary spastic paraplegia (SPG50)","volume":"53","author":"Eberhardt K,","year":"2021","unstructured":"Eberhardt K, et al. Generation and characterization of six human induced pluripotent stem cell lines (iPSC) from three families with AP4M1-associated hereditary spastic paraplegia (SPG50). Stem Cell Res 53, 102335 (2021).","journal-title":"Stem Cell Res"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"101575","DOI":"10.1016\/j.scr.2019.101575","article-title":"Generation and characterization of six human induced pluripotent stem cell lines (iPSC) from three families with AP4B1-associated hereditary spastic paraplegia (SPG47)","volume":"40","author":"Teinert J,","year":"2019","unstructured":"Teinert J, et al. Generation and characterization of six human induced pluripotent stem cell lines (iPSC) from three families with AP4B1-associated hereditary spastic paraplegia (SPG47). Stem Cell Res 40, 101575 (2019).","journal-title":"Stem Cell Res"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"9294","DOI":"10.1523\/JNEUROSCI.0642-19.2019","article-title":"Biallelic Mutations in TSC2 Lead to Abnormalities Associated with Cortical Tubers in Human iPSC-Derived Neurons","volume":"39","author":"Winden KD,","year":"2019","unstructured":"Winden KD, et al. Biallelic Mutations in TSC2 Lead to Abnormalities Associated with Cortical Tubers in Human iPSC-Derived Neurons. J Neurosci 39, 9294\u20139305 (2019).","journal-title":"J Neurosci"},{"key":"ref38","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/j.neuron.2013.05.029","article-title":"Rapid single-step induction of functional neurons from human pluripotent stem cells","volume":"78","author":"Zhang Y,","year":"2013","unstructured":"Zhang Y, et al. Rapid single-step induction of functional neurons from human pluripotent stem cells. Neuron 78, 785\u2013798 (2013).","journal-title":"Neuron"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"Article17","DOI":"10.2202\/1544-6115.1128","article-title":"A general framework for weighted gene co-expression network analysis","volume":"4","author":"Zhang B","year":"2005","unstructured":"Zhang B, Horvath S. A general framework for weighted gene co-expression network analysis. Stat Appl Genet Mol Biol 4, Article17 (2005).","journal-title":"Stat Appl Genet Mol Biol"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"e20763","DOI":"10.1371\/journal.pone.0020763","article-title":"A systems level, functional genomics analysis of chronic epilepsy","volume":"6","author":"Winden KD,","year":"2011","unstructured":"Winden KD, et al. A systems level, functional genomics analysis of chronic epilepsy. PLoS One 6, e20763 (2011).","journal-title":"PLoS One"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/1752-0509-1-54","article-title":"Eigengene networks for studying the relationships between co-expression modules","volume":"1","author":"Langfelder P","year":"2007","unstructured":"Langfelder P, Horvath S. Eigengene networks for studying the relationships between co-expression modules. BMC Syst Biol 1, 54 (2007).","journal-title":"BMC Syst Biol"},{"key":"ref42","doi-asserted-by":"crossref","first-page":"D687-D692","DOI":"10.1093\/nar\/gkab1028","article-title":"The reactome pathway knowledgebase 2022","volume":"50","author":"Gillespie M,","year":"2022","unstructured":"Gillespie M, et al. The reactome pathway knowledgebase 2022. Nucleic Acids Res 50, D687-D692 (2022).","journal-title":"Nucleic Acids Res"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1016\/0092-8674(93)90639-8","article-title":"cDNA cloning of component A of Rab geranylgeranyl transferase and demonstration of its role as a Rab escort protein","volume":"73","author":"Andres DA,","year":"1993","unstructured":"Andres DA, et al. cDNA cloning of component A of Rab geranylgeranyl transferase and demonstration of its role as a Rab escort protein. Cell 73, 1091\u20131099 (1993).","journal-title":"Cell"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"2111","DOI":"10.1016\/S0021-9258(17)42142-9","article-title":"REP-2, a Rab escort protein encoded by the choroideremia-like gene","volume":"269","author":"Cremers FP","year":"1994","unstructured":"Cremers FP, Armstrong SA, Seabra MC, Brown MS, Goldstein JL. REP-2, a Rab escort protein encoded by the choroideremia-like gene. J Biol Chem 269, 2111\u20132117 (1994).","journal-title":"J Biol Chem"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.1111\/j.1600-0854.2011.01240.x","article-title":"Small GTPase Rab12 regulates constitutive degradation of transferrin receptor","volume":"12","author":"Matsui T","year":"2011","unstructured":"Matsui T, Itoh T, Fukuda M. Small GTPase Rab12 regulates constitutive degradation of transferrin receptor. Traffic 12, 1432\u20131443 (2011).","journal-title":"Traffic"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/s13578-021-00543-2","article-title":"Golgi-associated Rab GTPases implicated in autophagy","volume":"11","author":"Lu Q","year":"2021","unstructured":"Lu Q, Wang PS, Yang L. Golgi-associated Rab GTPases implicated in autophagy. Cell Biosci 11, 35 (2021).","journal-title":"Cell Biosci"},{"key":"ref47","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/bs.ircmb.2014.12.002","article-title":"How Rab proteins determine Golgi structure","volume":"315","author":"Liu S","year":"2015","unstructured":"Liu S, Storrie B. How Rab proteins determine Golgi structure. Int Rev Cell Mol Biol 315, 1\u201322 (2015).","journal-title":"Int Rev Cell Mol Biol"},{"key":"ref48","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1038\/s41594-020-00518-w","article-title":"Atg9 is a lipid scramblase that mediates autophagosomal membrane expansion","volume":"27","author":"Matoba K,","year":"2020","unstructured":"Matoba K, et al. Atg9 is a lipid scramblase that mediates autophagosomal membrane expansion. Nat Struct Mol Biol 27, 1185\u20131193 (2020).","journal-title":"Nat Struct Mol Biol"},{"key":"ref49","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1038\/s41594-020-00520-2","article-title":"Structure, lipid scrambling activity and role in autophagosome formation of ATG9A","volume":"27","author":"Maeda S,","year":"2020","unstructured":"Maeda S, et al. Structure, lipid scrambling activity and role in autophagosome formation of ATG9A. Nat Struct Mol Biol 27, 1194\u20131201 (2020).","journal-title":"Nat Struct Mol Biol"},{"key":"ref50","doi-asserted-by":"crossref","first-page":"107837","DOI":"10.1016\/j.celrep.2020.107837","article-title":"Structure of Human ATG9A, the Only Transmembrane Protein of the Core Autophagy Machinery","volume":"31","author":"Guardia CM,","year":"2020","unstructured":"Guardia CM, et al. Structure of Human ATG9A, the Only Transmembrane Protein of the Core Autophagy Machinery. Cell Rep 31, 107837 (2020).","journal-title":"Cell Rep"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"4324","DOI":"10.1016\/j.molcel.2022.10.017","article-title":"ATG9A and ATG2A form a heteromeric complex essential for autophagosome formation","volume":"82","author":"Vliet AR","year":"2022","unstructured":"van Vliet AR, et al. ATG9A and ATG2A form a heteromeric complex essential for autophagosome formation. Mol Cell 82, 4324\u20134339 e4328 (2022).","journal-title":"Mol Cell"},{"key":"ref52","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1016\/j.ajhg.2019.07.011","article-title":"Mendelian Gene Discovery: Fast and Furious with No End in Sight","volume":"105","author":"Bamshad MJ","year":"2019","unstructured":"Bamshad MJ, Nickerson DA, Chong JX. Mendelian Gene Discovery: Fast and Furious with No End in Sight. Am J Hum Genet 105, 448\u2013455 (2019).","journal-title":"Am J Hum Genet"},{"key":"ref53","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1038\/s41431-019-0508-0","article-title":"Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database","volume":"28","author":"Nguengang Wakap S","year":"2020","unstructured":"Nguengang Wakap S, et al. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur J Hum Genet 28, 165\u2013173 (2020).","journal-title":"Eur J Hum Genet"},{"key":"ref54","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1186\/s13023-020-01574-7","article-title":"A retrospective review of the contribution of rare diseases to paediatric mortality in Ireland","volume":"15","author":"Gunne E","year":"2020","unstructured":"Gunne E, McGarvey C, Hamilton K, Treacy E, Lambert DM, Lynch SA. A retrospective review of the contribution of rare diseases to paediatric mortality in Ireland. Orphanet J Rare Dis 15, 311 (2020).","journal-title":"Orphanet J Rare Dis"},{"key":"ref55","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1038\/gim.2016.143","article-title":"The collective impact of rare diseases in Western Australia: an estimate using a population-based cohort","volume":"19","author":"Walker CE,","year":"2017","unstructured":"Walker CE, et al. The collective impact of rare diseases in Western Australia: an estimate using a population-based cohort. Genet Med 19, 546\u2013552 (2017).","journal-title":"Genet Med"},{"key":"ref56","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1186\/s13023-022-02561-w","article-title":"Carer burden in rare inherited diseases: a literature review and conceptual model","volume":"17","author":"Sandilands K","year":"2022","unstructured":"Sandilands K, Williams A, Rylands AJ. Carer burden in rare inherited diseases: a literature review and conceptual model. Orphanet J Rare Dis 17, 428 (2022).","journal-title":"Orphanet J Rare Dis"},{"key":"ref57","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1186\/s13023-022-02299-5","article-title":"The national economic burden of rare disease in the United States in 2019","volume":"17","author":"Yang G","year":"2022","unstructured":"Yang G, Cintina I, Pariser A, Oehrlein E, Sullivan J, Kennedy A. The national economic burden of rare disease in the United States in 2019. Orphanet J Rare Dis 17, 163 (2022).","journal-title":"Orphanet J Rare Dis"},{"key":"ref58","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1091\/mbc.E19-11-0658","article-title":"The FTS-Hook-FHIP (FHF) complex interacts with AP-4 to mediate perinuclear distribution of AP-4 and its cargo ATG9A","volume":"31","author":"Mattera R","year":"2020","unstructured":"Mattera R, Williamson CD, Ren X, Bonifacino JS. The FTS-Hook-FHIP (FHF) complex interacts with AP-4 to mediate perinuclear distribution of AP-4 and its cargo ATG9A. Mol Biol Cell 31, 963\u2013979 (2020).","journal-title":"Mol Biol Cell"},{"key":"ref59","doi-asserted-by":"crossref","first-page":"1860","DOI":"10.1091\/mbc.e11-09-0746","article-title":"Dynamic and transient interactions of Atg9 with autophagosomes, but not membrane integration, are required for autophagy","volume":"23","author":"Orsi A,","year":"2012","unstructured":"Orsi A, et al. Dynamic and transient interactions of Atg9 with autophagosomes, but not membrane integration, are required for autophagy. Mol Biol Cell 23, 1860\u20131873 (2012).","journal-title":"Mol Biol Cell"},{"key":"ref60","doi-asserted-by":"crossref","first-page":"3888","DOI":"10.1242\/jcs.03172","article-title":"Starvation and ULK1-dependent cycling of mammalian Atg9 between the TGN and endosomes","volume":"119","author":"Young AR,","year":"2006","unstructured":"Young AR, et al. Starvation and ULK1-dependent cycling of mammalian Atg9 between the TGN and endosomes. J Cell Sci 119, 3888\u20133900 (2006).","journal-title":"J Cell Sci"},{"key":"ref61","doi-asserted-by":"crossref","first-page":"e202009194","DOI":"10.1083\/jcb.202009194","article-title":"Transmembrane phospholipid translocation mediated by Atg9 is involved in autophagosome formation","volume":"220","author":"Orii M","year":"2021","unstructured":"Orii M, Tsuji T, Ogasawara Y, Fujimoto T. Transmembrane phospholipid translocation mediated by Atg9 is involved in autophagosome formation. J Cell Biol 220, e202009194 (2021).","journal-title":"J Cell Biol"},{"key":"ref62","first-page":"1","article-title":"--Atg9 interactions via its transmembrane domains are required for phagophore expansion during autophagy","author":"Chumpen Ramirez S","year":"2022","unstructured":"Chumpen Ramirez S, et al. --Atg9 interactions via its transmembrane domains are required for phagophore expansion during autophagy. Autophagy, 1\u201320 (2022).","journal-title":"Autophagy"},{"key":"ref63","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1038\/nature04724","article-title":"Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice","volume":"441","author":"Hara T,","year":"2006","unstructured":"Hara T, et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885\u2013889 (2006).","journal-title":"Nature"},{"key":"ref64","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1038\/nature04723","article-title":"Loss of autophagy in the central nervous system causes neurodegeneration in mice","volume":"441","author":"Komatsu M,","year":"2006","unstructured":"Komatsu M, et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880\u2013884 (2006).","journal-title":"Nature"},{"key":"ref65","doi-asserted-by":"crossref","first-page":"14489","DOI":"10.1073\/pnas.0701311104","article-title":"Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration","volume":"104","author":"Komatsu M,","year":"2007","unstructured":"Komatsu M, et al. Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration. Proc Natl Acad Sci U S A 104, 14489\u201314494 (2007).","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref66","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1083\/jcb.56.3.713","article-title":"Fine structure of nerve fibers and growth cones of isolated sympathetic neurons in culture","volume":"56","author":"Bunge MB","year":"1973","unstructured":"Bunge MB. Fine structure of nerve fibers and growth cones of isolated sympathetic neurons in culture. J Cell Biol 56, 713\u2013735 (1973).","journal-title":"J Cell Biol"},{"key":"ref67","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1083\/jcb.121.2.305","article-title":"Products of endocytosis and autophagy are retrieved from axons by regulated retrograde organelle transport","volume":"121","author":"Hollenbeck PJ","year":"1993","unstructured":"Hollenbeck PJ. Products of endocytosis and autophagy are retrieved from axons by regulated retrograde organelle transport. J Cell Biol 121, 305\u2013315 (1993).","journal-title":"J Cell Biol"},{"key":"ref68","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.devcel.2014.06.001","article-title":"Autophagosome biogenesis in primary neurons follows an ordered and spatially regulated pathway","volume":"30","author":"Maday S","year":"2014","unstructured":"Maday S, Holzbaur EL. Autophagosome biogenesis in primary neurons follows an ordered and spatially regulated pathway. Dev Cell 30, 71\u201385 (2014).","journal-title":"Dev Cell"},{"key":"ref69","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1083\/jcb.201106120","article-title":"Autophagosomes initiate distally and mature during transport toward the cell soma in primary neurons","volume":"196","author":"Maday S","year":"2012","unstructured":"Maday S, Wallace KE, Holzbaur EL. Autophagosomes initiate distally and mature during transport toward the cell soma in primary neurons. J Cell Biol 196, 407\u2013417 (2012).","journal-title":"J Cell Biol"},{"key":"ref70","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1016\/j.celrep.2016.09.054","article-title":"Impaired Mitochondrial Dynamics and Mitophagy in Neuronal Models of Tuberous Sclerosis Complex","volume":"17","author":"Ebrahimi-Fakhari D,","year":"2016","unstructured":"Ebrahimi-Fakhari D, et al. Impaired Mitochondrial Dynamics and Mitophagy in Neuronal Models of Tuberous Sclerosis Complex. Cell Rep 17, 1053\u20131070 (2016).","journal-title":"Cell Rep"},{"key":"ref71","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1021\/acschemneuro.6b00029","article-title":"Central Nervous System Multiparameter Optimization Desirability: Application in Drug Discovery","volume":"7","author":"Wager TT","year":"2016","unstructured":"Wager TT, Hou X, Verhoest PR, Villalobos A. Central Nervous System Multiparameter Optimization Desirability: Application in Drug Discovery. ACS Chem Neurosci 7, 767\u2013775 (2016).","journal-title":"ACS Chem Neurosci"},{"key":"ref72","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1038\/nrm2728","article-title":"Rab GTPases as coordinators of vesicle traffic","volume":"10","author":"Stenmark H","year":"2009","unstructured":"Stenmark H. Rab GTPases as coordinators of vesicle traffic. Nat Rev Mol Cell Biol 10, 513\u2013525 (2009).","journal-title":"Nat Rev Mol Cell Biol"},{"key":"ref73","doi-asserted-by":"crossref","first-page":"a022616","DOI":"10.1101\/cshperspect.a022616","article-title":"Rab proteins and the compartmentalization of the endosomal system","volume":"6","author":"Wandinger-Ness A","year":"2014","unstructured":"Wandinger-Ness A, Zerial M. Rab proteins and the compartmentalization of the endosomal system. Cold Spring Harb Perspect Biol 6, a022616 (2014).","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"ref74","doi-asserted-by":"crossref","first-page":"6629","DOI":"10.1523\/JNEUROSCI.1610-04.2004","article-title":"A complete genetic analysis of neuronal Rab3 function","volume":"24","author":"Schluter OM","year":"2004","unstructured":"Schluter OM, Schmitz F, Jahn R, Rosenmund C, Sudhof TC. A complete genetic analysis of neuronal Rab3 function. J Neurosci 24, 6629\u20136637 (2004).","journal-title":"J Neurosci"},{"key":"ref75","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/embor.2013.32","article-title":"Rab12 regulates mTORC1 activity and autophagy through controlling the degradation of amino-acid transporter PAT4","volume":"14","author":"Matsui T","year":"2013","unstructured":"Matsui T, Fukuda M. Rab12 regulates mTORC1 activity and autophagy through controlling the degradation of amino-acid transporter PAT4. EMBO Rep 14, 450\u2013457 (2013).","journal-title":"EMBO Rep"},{"key":"ref76","doi-asserted-by":"crossref","first-page":"ar102","DOI":"10.1091\/mbc.E21-09-0473","article-title":"AP-4 regulates neuronal lysosome composition, function, and transport via regulating export of critical lysosome receptor proteins at the trans-Golgi network","volume":"33","author":"Majumder P","year":"2022","unstructured":"Majumder P, Edmison D, Rodger C, Patel S, Reid E, Gowrishankar S. AP-4 regulates neuronal lysosome composition, function, and transport via regulating export of critical lysosome receptor proteins at the trans-Golgi network. Mol Biol Cell 33, ar102 (2022).","journal-title":"Mol Biol Cell"},{"key":"ref77","doi-asserted-by":"crossref","first-page":"3588","DOI":"10.1093\/hmg\/ddw204","article-title":"Reduction of TMEM97 increases NPC1 protein levels and restores cholesterol trafficking in Niemann-pick type C1 disease cells","volume":"25","author":"Ebrahimi-Fakhari D","year":"2016","unstructured":"Ebrahimi-Fakhari D, et al. Reduction of TMEM97 increases NPC1 protein levels and restores cholesterol trafficking in Niemann-pick type C1 disease cells. Hum Mol Genet 25, 3588\u20133599 (2016).","journal-title":"Hum Mol Genet"},{"key":"ref78","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1093\/bioinformatics\/btp053","article-title":"Testing significance relative to a fold-change threshold is a TREAT","volume":"25","author":"McCarthy DJ","year":"2009","unstructured":"McCarthy DJ, Smyth GK. Testing significance relative to a fold-change threshold is a TREAT. Bioinformatics 25, 765\u2013771 (2009).","journal-title":"Bioinformatics"},{"year":"2016","author":"Chen Y","key":"ref79","unstructured":"Chen Y, Lun AT, Smyth GK. From reads to genes to pathways: differential expression analysis of RNA-Seq experiments using Rsubread and the edgeR quasi-likelihood pipeline. F1000Res 5, 1438 (2016)."},{"key":"ref80","first-page":"100141","article-title":"clusterProfiler 4.0: A universal enrichment tool for interpreting omics data","volume":"2","author":"Wu T,","year":"2021","unstructured":"Wu T, et al. clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation (Camb) 2, 100141 (2021).","journal-title":"Innovation (Camb)"},{"key":"ref81","doi-asserted-by":"crossref","first-page":"R106","DOI":"10.1186\/gb-2010-11-10-r106","article-title":"Differential expression analysis for sequence count data","volume":"11","author":"Anders S","year":"2010","unstructured":"Anders S, Huber W. Differential expression analysis for sequence count data. Genome Biol 11, R106 (2010).","journal-title":"Genome Biol"},{"key":"ref82","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie ME,","year":"2015","unstructured":"Ritchie ME, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 43, e47 (2015).","journal-title":"Nucleic Acids Res"},{"key":"ref83","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1186\/1471-2105-9-559","article-title":"WGCNA: an R package for weighted correlation network analysis","volume":"9","author":"Langfelder P","year":"2008","unstructured":"Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics 9, 559 (2008).","journal-title":"BMC Bioinformatics"},{"key":"ref84","doi-asserted-by":"crossref","first-page":"i11","DOI":"10.18637\/jss.v046.i11","article-title":"Fast R Functions for Robust Correlations and Hierarchical Clustering","volume":"46","author":"Langfelder P","year":"2012","unstructured":"Langfelder P, Horvath S. Fast R Functions for Robust Correlations and Hierarchical Clustering. J Stat Softw 46, i11 (2012).","journal-title":"J Stat Softw"},{"key":"ref85","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1038\/nmeth.2834","article-title":"Minimal, encapsulated proteomic-sample processing applied to copy-number estimation in eukaryotic cells","volume":"11","author":"Kulak NA","year":"2014","unstructured":"Kulak NA, Pichler G, Paron I, Nagaraj N, Mann M. Minimal, encapsulated proteomic-sample processing applied to copy-number estimation in eukaryotic cells. Nat Methods 11, 319\u2013324 (2014).","journal-title":"Nat Methods"},{"key":"ref86","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1038\/nbt.1511","article-title":"MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification","volume":"26","author":"Cox J","year":"2008","unstructured":"Cox J, Mann M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol 26, 1367\u20131372 (2008).","journal-title":"Nat Biotechnol"},{"key":"ref87","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1038\/s41587-021-00968-7","article-title":"MaxDIA enables library-based and library-free data-independent acquisition proteomics","volume":"39","author":"Sinitcyn P,","year":"2021","unstructured":"Sinitcyn P, et al. MaxDIA enables library-based and library-free data-independent acquisition proteomics. Nat Biotechnol 39, 1563\u20131573 (2021).","journal-title":"Nat Biotechnol"},{"key":"ref88","doi-asserted-by":"crossref","first-page":"2513","DOI":"10.1074\/mcp.M113.031591","article-title":"Accurate proteome-wide label-free quantification by delayed normalization and maximal peptide ratio extraction, termed MaxLFQ","volume":"13","author":"Cox J","year":"2014","unstructured":"Cox J, Hein MY, Luber CA, Paron I, Nagaraj N, Mann M. Accurate proteome-wide label-free quantification by delayed normalization and maximal peptide ratio extraction, termed MaxLFQ. Mol Cell Proteomics 13, 2513\u20132526 (2014).","journal-title":"Mol Cell Proteomics"},{"key":"ref89","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1093\/biostatistics\/kxj037","article-title":"Adjusting batch effects in microarray expression data using empirical Bayes methods","volume":"8","author":"Johnson WE","year":"2007","unstructured":"Johnson WE, Li C, Rabinovic A. Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics 8, 118\u2013127 (2007).","journal-title":"Biostatistics"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/www.researchsquare.com\/article\/rs-3036166\/v1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.researchsquare.com\/article\/rs-3036166\/v1.html","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,19]],"date-time":"2024-01-19T08:22:43Z","timestamp":1705652563000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.researchsquare.com\/article\/rs-3036166\/v1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,12]]},"references-count":89,"URL":"https:\/\/doi.org\/10.21203\/rs.3.rs-3036166\/v1","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1038\/s41467-023-44264-1","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2023,6,12]]},"subtype":"preprint"}}