Prideapplication/xmlftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/04/PXD061057/FS1156_timstofPro_PASEF_Maxqaunt_ProteinGroups.xlsxftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/04/PXD061057/IP_ProteinGroups.xlsxftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/04/PXD061057/FS1156.zipprimaryOK200fs2644@cumc.columbia.eduRajesh SoniMass SpectrometryBottom-up proteomicsAlzheimer’s diseaseProtein-protein interactionGeneticsSorl1Microgliahttps://www.ebi.ac.uk/pride/archive/projects/PXD061057THP-1 cells (ATCC TIB-202) were cultured in RPMI (Gibco 61870127) with 10% FBS and 1% penicillin-streptomycin. 30 × 10⁶ cells per sample were harvested, washed, and lysed in IP lysis buffer (30mM Tris-HCl pH 7.4, 120mM NaCl, 10% glycerol, 2mM EDTA, 2mM KCl, 1% NP-40, protease inhibitors, PMSF). Lysates were centrifuged, and supernatants were collected for immunoprecipitation (IP). Immunoprecipitation & Sample Preparation: IP-SORL1 (Proteintech 22592-1-AP) and IgG control were incubated overnight at 4°C, followed by Dynabeads pulldown (2 hours, 4°C). Immune complexes were washed, eluted in 2× sample buffer, and analyzed by Western blot or mass spectrometry. 200 ng of peptides were analyzed on timsTOF Pro LC-MS/MS using a reversed-phase C18 column. Peptides were separated with an optimized mobile phase gradient before MS detection.PrideLC-MS/MS data analysis was done using Maxquant and Andromeda for database searches. Searches were performed with the reference human proteome database from Uniport, with specified false discovery rates (FDR) and modifications. The output files from Maxqunt were submitted to Perseus-framework for standard protein-protein interaction analysis.ProteomicsFalak SherAssistant Professor of Neurological Sciences Columbia UniversityPARTIALHomo Sapiens (human)41942750 Haq I, Ngo JC, Roy N, Lee E, Choudhury MA, Soni RK, Teich AF, Mayeux RP, De Jager PL, He Y, Wu X, Bennett DA, Olah M, Sher F. Alzheimer's disease risk protein SorLA regulates ER homeostasis and lipid metabolism in human microglia, with conserved effects in neurons. Acta Neuropathol. 2026 151(1):37 10.1007/s00401-026-03002-9rs3869@cumc.columbia.eduColumbia University Medical centerUnited StatesMicroglial dysfunction is a hallmark of Alzheimer's disease (AD), yet the molecular mechanisms driving these impairments remain poorly defined. Genetic studies implicate several AD-associated genes in regulating microglial activity, including SORL1, which encodes the sorting receptor SorLA. Although SorLA is highly expressed in microglia, its functional role in cellular homeostasis has remained unclear. Here, we investigated SorLA function using human brain tissue, primary microglia from rapid autopsies, and CRISPR-engineered human iPSC-derived microglia and neurons. Integrated multi-omics analyses, including single-cell RNA sequencing, lipidomics, and proteomics, together with biochemical and functional assays, revealed that SorLA deficiency induces endoplasmic reticulum (ER) stress and interferon signaling, promotes lipid droplet accumulation, and impairs phagocytic and immune functions. Protein co-complex mapping and structural modeling identified ER-associated proteins co-enriched with SorLA, including SUN2, calnexin (CANX), and multiple COPI complex components (COPA, COPB1, COPG1, ARCN1), implicating SorLA in ER proteostasis and intracellular trafficking. Notably, SORL1 deletion in iPSC-derived neurons recapitulated key phenotypes observed in microglia, including lipid droplet accumulation and SorLA-SUN2 co-immunoprecipitation, indicating that this ER-associated pathway operates across distinct brain cell types. Together, these findings identify an ER-related role for SorLA that extends beyond its established function in endocytic trafficking. Loss of SorLA triggers maladaptive stress responses, perturbs lipid handling, and compromises cellular resilience, thereby contributing to AD-relevant cellular dysfunction.Alzheimer's disease risk protein SorLA regulates ER homeostasis and lipid metabolism in human microglia, with conserved effects in neurons.Haq Imdadul I, Ngo Jason C JC, Roy Nainika N, Lee Emily E, Choudhury Muniyat A MA, Soni Rajesh K RK, Teich Andrew F AF, Mayeux Richard P RP, De Jager Philip L PL, He Ye Y, Wu Xuebing X, Bennett David A DA, Olah Marta M, Sher Falak FfalseIdentification of SORL1 Binding Partners via Immunoprecipitation-Mass Spectrometry in THP-1 Cells.SORL1 (Sortilin-Related Receptor 1) is a key player in endosomal trafficking and has been implicated in neurodegenerative disorders. To identify SORL1 binding partners, we performed immunoprecipitation (IP) of SORL1, followed by mass spectrometry-based proteomic analysis. THP-1 cell lysates were used as the source material for immunoprecipitation, and IgG controls were included to filter out non-specific interactions. The resulting datasets provide insights into SORL1-associated protein complexes, offering potential targets for further functional studies.2026-04-132025-02-21PXD061057NEWT:1773NEWT:6945NEWT:3555NEWT:38783NEWT:8727NEWT:1182590NEWT:8726NEWT:2NEWT:157546NEWT:10090NEWT:935293NEWT:749200NEWT:35554NEWT:4120NEWT:5693NEWT:9417NEWT:347515NEWT:8724NEWT:1216979NEWT:307972NEWT:92867NEWT:8723NEWT:990346NEWT:544496NEWT:5334NEWT:145953NEWT:257309NEWT:5180NEWT:284812NEWT:115104NCBITaxon:1313NEWT:1081927NEWT:43330NEWT:67825NEWT:44544NEWT:13076NEWT:1249668NEWT:373995NEWT:544404NEWT:3702NEWT:8839NEWT:317NEWT:4232NEWT:990119NEWT:1736309NEWT:4113NEWT:7227NEWT:11298NEWT:7469NEWT:885318NEWT:171101NEWT:4081NEWT:876138NEWT:554NEWT:5691NEWT:98334NEWT:408170NEWT:260710NEWT:627025NEWT:3708NEWT:106592NEWT:237561NEWT:9913NEWT:10036NEWT:4100NEWT:7574NEWT:1351NEWT:1076NEWT:6763NEWT:7215NEWT:803NEWT:8030NEWT:380394NEWT:272563NEWT:507601NEWT:1639NEWT:188229NEWT:4909NCBITaxon:79857NEWT:95648NEWT:746360NEWT:6239NEWT:1589NEWT:135588NEWT:135622NEWT:216257NEWT:6915NEWT:9986NEWT:101510NEWT:95486NEWT:3880NEWT:58002NEWT:9103NEWT:4577NEWT:5664NEWT:2157NEWT:146479NEWT:1911079NEWT:1000589NEWT:145943NEWT:1902NEWT:85962NEWT:160488NEWT:317447NEWT:3635NEWT:7955NCBITaxon:2NEWT:1480154NEWT:7959NEWT:2261NEWT:3197NEWT:9615NEWT:884019NEWT:4565NEWT:1264690NEWT:169963NCBITaxon:38727NEWT:36329NEWT:34305NEWT:59729NCBITaxon:183674NEWT:224308NEWT:626528NEWT:139927NEWT:4558NEWT:9606NEWT:367830NEWT:157295NEWT:243230NEWT:931281NEWT:373153NEWT:7029NEWT:1283300NEWT:334747NEWT:470NCBITaxon:79824NCBITaxon:4563NEWT:3218NEWT:5759NEWT:9838NCBITaxon:9615NEWT:1736231NEWT:1193501NEWT:3055NEWT:6287NEWT:2242NEWT:6326NEWT:9796NEWT:2762NEWT:5476NEWT:1174673NEWT:562NEWT:260707NEWT:287NEWT:10117NEWT:10239NEWT:10116NEWT:1280NEWT:1836NEWT:1735272NEWT:29760NEWT:260705NEWT:80863NEWT:1148NEWT:4932NEWT:70448NEWT:9825NEWT:3603NEWT:698936NEWT:2759NEWT:39946NEWT:11676NEWT:9823NEWT:100226NCBITaxon:6073NEWT:4530NEWT:4896NEWT:6279NEWT:7370NEWT:573NEWT:6282NEWT:7091NEWT:113450641942750