Affinage

PICALM

Phosphatidylinositol-binding clathrin assembly protein · UniProt Q13492

Length
652 aa
Mass
70.8 kDa
Annotated
2026-06-10
100 papers in source corpus 27 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PICALM is a clathrin-adaptor protein that drives clathrin-mediated endocytosis through its PIP2-binding domain and C-terminal clathrin-association motif, governing the internalization of multiple cell-surface cargoes (PMID:22952941, PMID:25552701). Its best-defined housekeeping role is in transferrin receptor uptake and iron homeostasis: PICALM loss raises surface TfR, lowers intracellular iron, and impairs erythroid maturation, with the PIP2-binding domain essential for clathrin coat maturation and erythroid development in vivo (PMID:22952941, PMID:22363754, PMID:25552701), consistent with the hematopoietic and iron-metabolism defects of mouse loss-of-function alleles (PMID:12832620). Beyond endocytosis, PICALM controls autophagy by regulating endocytosis of the SNARE proteins VAMP2/3/8, thereby setting autophagosome formation and degradation and clearance of the autophagy substrate tau (PMID:25241929), and acts within an AP2/PICALM cargo receptor that binds LC3 to route APP-CTF toward autophagic degradation (PMID:24067654). PICALM also directs maturation of lysosomal enzymes, including cathepsin D processing (PMID:34311200), and shapes cellular cholesterol and LDL-receptor handling (PMID:26075887). In Alzheimer's-disease-relevant contexts, PICALM binds APP via its NPXY/Y682ENPTY687 motif to control APP internalization, nanoscale dynamics, and Aβ generation (PMID:22539346, PMID:31300465, PMID:37726569), and at the blood-brain barrier it links LRP1 and ABCB1/P-glycoprotein to drive Rab5/Rab11-dependent transcytosis and clearance of Aβ across brain endothelium (PMID:26005850, PMID:30041013); pharmacological elevation of endothelial PICALM with artesunate reduces Aβ pathology in an endothelial-PICALM-dependent manner (PMID:36707892). In microglia, an Alzheimer's-risk allele reduces PU.1-driven PICALM expression, impairing phagocytosis of Aβ and myelin debris and causing lipid droplet accumulation (PMID:40903578), while Picalm haploinsufficiency aggravates tau pathology in vivo (PMID:31925534).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2003 High

    Established that PICALM is genetically essential in vivo by showing loss-of-function alleles cause hematopoietic, growth, and iron-metabolism defects, framing PICALM as a non-redundant endocytic regulator.

    Evidence ENU mutagenesis screen with molecularly defined Picalm mutant alleles in mice

    PMID:12832620

    Open questions at the time
    • Did not identify the specific cargo or molecular step disrupted
    • Mechanism linking endocytosis defect to phenotype not resolved
  2. 2012 High

    Defined the molecular cargo behind the iron phenotype, showing PICALM drives clathrin-mediated transferrin receptor endocytosis required for erythroid maturation.

    Evidence PICALM-deficient/KO mice and MEFs with retroviral rescue, C-terminal deletion mutants, transferrin endocytosis and iron assays

    PMID:22363754 PMID:22952941

    Open questions at the time
    • C-terminal clathrin-binding region mapped but structural basis not resolved
    • Did not address non-erythroid cargoes
  3. 2014 High

    Demonstrated the PIP2-binding domain is the essential functional element for TfR endocytosis and erythroid development and required for clathrin coat maturation.

    Evidence Conditional Picalm KO mice with PIP2-domain mutant, freeze-etch EM, Jak2(V617F) polycythemia vera rescue

    PMID:25552701

    Open questions at the time
    • Cell-type specificity of cargo selection not fully explained
    • Structural mechanism of coat maturation incomplete
  4. 2014 High

    Extended PICALM beyond cargo uptake to autophagy regulation by identifying SNARE proteins (VAMP2/3/8) as endocytic substrates affecting distinct autophagy stages.

    Evidence siRNA/overexpression in cell lines plus zebrafish transgenic tau-clearance models

    PMID:25241929

    Open questions at the time
    • Direct interaction interface with each VAMP not defined
    • Stage-specific contribution of each SNARE not separated
  5. 2013 High

    Showed PICALM acts in an AP2-containing autophagic cargo receptor that bridges LC3 and APP-CTF, providing a molecular route from endocytosis to autophagic degradation.

    Evidence Affinity purification/MS, co-IP, siRNA knockdown, live imaging

    PMID:24067654

    Open questions at the time
    • Stoichiometry and direct LC3-binding determinant on PICALM vs AP2 not resolved
    • In vivo relevance not tested here
  6. 2012 High

    Connected PICALM to amyloid biology by showing it controls APP internalization and bidirectionally sets Aβ production in cells and APP/PS1 mice.

    Evidence siRNA/overexpression in N2a-APP cells, AAV8 shRNA/cDNA in APP/PS1 mice, colocalization and ELISA

    PMID:22539346

    Open questions at the time
    • Did not define the APP-PICALM binding determinant
    • Did not distinguish neuronal vs vascular contributions
  7. 2015 High

    Identified PICALM as a blood-brain-barrier clearance factor that internalizes LRP1-bound Aβ through Rab5/Rab11 endosomes for transcytosis.

    Evidence Human and iPSC endothelial monolayers, Picalm-deficient mice with adenoviral rescue, live imaging

    PMID:26005850

    Open questions at the time
    • Did not identify all endothelial partners coordinating transcytosis
    • Directionality control of transcytosis not fully resolved
  8. 2013 Medium

    Linked PICALM to tau pathology, showing PICALM is proteolytically cleaved and depleted in AD brain and associates with PHF-tau.

    Evidence Western blot, in vitro calpain/caspase cleavage assay, IHC, co-IP from AD brain

    PMID:23589030

    Open questions at the time
    • Co-IP without reciprocal validation; directness of PICALM-tau interaction unclear
    • Functional consequence of cleavage not established
  9. 2015 Medium

    Broadened PICALM's lipid trafficking role to cholesterol homeostasis and LDL-receptor handling.

    Evidence Transcriptomics, GC-MS cholesterol quantification, isotopic labeling, flow cytometry for LDLR internalization

    PMID:26075887

    Open questions at the time
    • Mechanism by which PICALM alters cholesterol-gene expression unknown
    • Single lab, single cell context
  10. 2018 Medium

    Provided the endothelial protein-interaction basis for Aβ clearance, showing PICALM physically links LRP1 and ABCB1/P-gp.

    Evidence Co-IP, co-immunostaining, dual ABCB1/LRP1 inhibition in brain endothelium

    PMID:30041013

    Open questions at the time
    • Co-IP/co-staining without direct binding-site mapping
    • Whether interaction is direct or scaffolded not resolved
  11. 2019 Medium

    Defined the APP-PICALM interaction at the NPXY motif and showed PTB-domain adaptors (Numb, JIP1b, GULP1) tune the interaction, surface APP, and PICALM nuclear shuttling.

    Evidence Co-IP with APP NPXY mutation, FACS, internalization assays, fluorescence microscopy

    PMID:31300465

    Open questions at the time
    • Functional consequence of PICALM nuclear shuttling unknown
    • Single lab without in vivo confirmation
  12. 2020 High

    Established genetic epistasis with tau pathology, showing Picalm haploinsufficiency aggravates tau accumulation and motor deficits in vivo.

    Evidence Tg30 x Picalm+/- mouse cross, behavior, IHC, autophagy-marker Western blots

    PMID:31925534

    Open questions at the time
    • Did not separate autophagy from endocytic contributions to tau handling
    • Cell-type origin of effect not dissected
  13. 2020 Medium

    Positioned PICALM as a convergence node for AD risk by showing its overexpression rescues APOE4-induced endocytic defects across yeast and human astrocytes.

    Evidence Isogenic APOE3/APOE4 iPSC astrocytes and yeast Yap1802p rescue, endocytosis assays

    PMID:33027662

    Open questions at the time
    • Molecular target of the APOE4 endocytic defect not identified
    • Astrocyte-specific consequences in vivo untested
  14. 2021 Medium

    Showed PICALM is required for lysosomal enzyme maturation, linking it to endosome-to-lysosome processing and autophagy.

    Evidence CRISPR/Cas9 PICALM KO in HeLa, proteomics of endosome fractions, cathepsin D Western blot

    PMID:34311200

    Open questions at the time
    • Mechanism connecting endocytic defect to cathepsin D mis-processing unclear
    • Single cell type
  15. 2023 Medium

    Resolved PICALM's subsynaptic organization, showing it forms nanodomains at pre- and postsynaptic zones and controls APP nanoscale dynamics via the APP C-terminal motif.

    Evidence STORM/PALM super-resolution imaging, single-particle tracking, APP C-terminal mutants in neurons

    PMID:37726569

    Open questions at the time
    • Functional readout of altered APP diffusion not measured
    • Single lab
  16. 2023 High

    Provided in vivo therapeutic proof-of-concept that elevating endothelial PICALM clears Aβ, with the effect strictly dependent on endothelial PICALM.

    Evidence FDA drug screen identifying artesunate, Picalm+/-;5XFAD and endothelial conditional KO mice, Aβ ELISA, CBF

    PMID:36707892

    Open questions at the time
    • Mechanism by which artesunate raises PICALM transcription incompletely defined
    • Long-term safety/efficacy not addressed
  17. 2025 High

    Connected the AD-risk variant to microglial dysfunction, showing rs10792832 reduces PU.1-driven PICALM expression, impairing phagocytosis and causing lipid droplet accumulation.

    Evidence Allele-specific open-chromatin mapping in iPSC microglia/neurons/astrocytes, genetic and pharmacological perturbation, phagocytosis and lipid droplet assays

    PMID:40903578

    Open questions at the time
    • How reduced endocytosis mechanistically drives lipid droplet buildup not fully resolved
    • Other risk-allele effects on non-microglial cells not addressed
  18. 2024 Medium

    Extended PICALM's functional reach to peripheral systems, implicating it in HIV-1 entry, doxorubicin cardiotoxicity, and adipocyte insulin/GLUT4 signaling.

    Evidence CRISPR screen in CD4+ T cells; scRNA-seq plus Picalm depletion in doxorubicin cardiotoxicity; siRNA in 3T3-L1 adipocytes with GLUT4 and insulin-signaling assays

    PMID:38935046 PMID:38957789 PMID:39182843

    Open questions at the time
    • Whether these reflect a single shared endocytic mechanism unclear
    • Direct molecular partners in each context not mapped
  19. 2026 Medium

    Tied PICALM-dependent endocytosis to actin remodeling and myogenesis by showing actin stabilization rescues differentiation in PICALM-deficient myoblasts.

    Evidence siRNA in C2C12/primary myocytes, EGF internalization, plasma membrane proteomics, Jasplakinolide rescue

    PMID:41833602

    Open questions at the time
    • Direct physical link between PICALM and actin machinery not demonstrated
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PICALM selects among its diverse cargoes (TfR, APP, SNAREs, LDLR, GLUT4) in a cell-type-specific manner, and the structural determinants distinguishing these interactions, remain unresolved.
  • No unified structural model of cargo selectivity
  • Isoform-specific functions (e.g., PICALML) largely uncharacterized
  • Mechanism coupling PICALM endocytosis to autophagy and lysosomal maturation not fully defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0008289 lipid binding 2 GO:0038024 cargo receptor activity 1
Localization
GO:0005886 plasma membrane 4 GO:0005768 endosome 3 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-1643685 Disease 4 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-9612973 Autophagy 3 R-HSA-9609507 Protein localization 2
Partners
ABCB1AP2APPLC3LRP1VAMP2VAMP3VAMP8
Complex memberships
AP2/PICALM clathrin adaptor complex

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 PICALM regulates clathrin-dependent internalization of Aβ bound to LRP1 at the blood-brain barrier and guides Aβ trafficking through Rab5 and Rab11 endosomal compartments, leading to transcytosis and clearance of Aβ across brain endothelium. Endothelial PICALM deficiency diminishes Aβ clearance and accelerates Aβ pathology, reversible by endothelial PICALM re-expression. Human brain endothelial monolayers, Picalm-deficient mice, adenoviral PICALM re-expression, iPSC-derived endothelial cells, live imaging, immunofluorescence Nature neuroscience High 26005850
2014 PICALM/CALM modulates autophagy by regulating the endocytosis of SNARE proteins VAMP2, VAMP3, and VAMP8, which affect distinct stages of autophagy from autophagosome formation to degradation. CALM overexpression or depletion alters tau clearance (an autophagy substrate) both in vitro and in vivo in zebrafish transgenic models. siRNA knockdown, overexpression in cell lines, zebrafish transgenic models, endocytosis assays for SNARE proteins Nature communications High 25241929
2013 PICALM forms a complex with adaptor protein AP2 that functions as an autophagic cargo receptor; AP2/PICALM binds LC3 (identified by affinity purification/mass spectrometry) and cross-links LC3 with APP-CTF, directing APP-CTF from the endocytic pathway to autophagic degradation. AP2 knockdown reduces autophagy-mediated APP-CTF degradation. Affinity purification followed by mass spectrometry, co-immunoprecipitation, siRNA knockdown, live imaging Proceedings of the National Academy of Sciences of the United States of America High 24067654
2012 PICALM co-localizes with APP in intracellular vesicles after endocytosis. PICALM knockdown reduces APP internalization and Aβ generation; PICALM overexpression increases APP internalization and Aβ production. In vivo AAV-mediated PICALM manipulation in APP/PS1 mice bidirectionally alters soluble and insoluble Aβ levels and amyloid plaque load. siRNA knockdown, PICALM overexpression in N2a-APP cells, AAV8 gene transfer (shRNA and cDNA) in APP/PS1 mice, colocalization imaging, ELISA The Journal of biological chemistry High 22539346
2013 PICALM is abnormally cleaved in AD brains by calpain or caspase (demonstrated in vitro); full-length PICALM is decreased in AD. PICALM co-localizes with neurofibrillary tangles containing conformationally abnormal hyperphosphorylated tau, and PHF-tau proteins co-immunoprecipitate with PICALM. Western blotting with anti-PICALM antibodies, in vitro calpain/caspase activation assay, immunohistochemistry, co-immunoprecipitation Acta neuropathologica Medium 23589030
2012 PICALM plays a critical role in transferrin receptor (TfR) internalization and iron homeostasis. PICALM-deficient MEFs show increased surface TfR expression, decreased intracellular iron, and reduced proliferation, all rescued by retroviral PICALM re-expression. C-terminal PICALM residues are critical for clathrin association and inhibitory effect on TfR internalization. PICALM overexpression and knockdown/deficient MEFs from fit1 mice, retroviral rescue, flow cytometry, iron supplementation experiments, C-terminal deletion mutants PloS one High 22952941
2012 CALM/PICALM is required for clathrin-mediated endocytosis of transferrin and for erythroid maturation in mice. CALM-deficient mice exhibit severe anemia and impaired iron content in erythroid precursors; CALM-deficient erythroid cells and embryonic fibroblasts show impaired clathrin-mediated transferrin endocytosis. CALM-deficient mouse model, transferrin endocytosis assays in erythroid cells and embryonic fibroblasts, histological analysis PloS one High 22363754
2014 PICALM PIP2-binding domain is necessary for transferrin receptor endocytosis in erythroblasts and absolutely essential for erythroid development. PICALM functions as a cell-type-specific regulator of transferrin receptor endocytosis in erythroid cells, and is required for efficient clathrin coat maturation (shown by freeze-etch EM). Picalm deletion abrogates disease phenotype in a Jak2(V617F) polycythemia vera mouse model. Conditional Picalm knockout mice, PIP2-binding domain mutant, freeze-etch electron microscopy, live-cell imaging, erythroid culture system, Jak2(V617F) knock-in mouse model Haematologica High 25552701
2018 PICALM physically associates with both ABCB1/P-glycoprotein and LRP1 at brain endothelium (shown by co-immunoprecipitation and co-immunostaining), functionally linking these two Aβ clearance proteins and guiding their coordinated transcytosis of Aβ through endothelial cells. Co-immunoprecipitation, co-immunostaining, dual inhibition of ABCB1/P-gp and LRP1 Brain, behavior, and immunity Medium 30041013
2016 PICALM depletion by siRNA in H4 neuroglioma cells reduces functional clathrin-mediated endocytosis (measured by Alexa488-transferrin uptake), reduces intracellular APP, β-CTF, and secreted sAPPβ, and decreases BACE1 mRNA and protein levels. PICALM depletion alters intracellular distribution of clathrin. siRNA knockdown of PICALM and clathrin, Western blotting, ELISA, immunohistochemistry, flow cytometry for transferrin uptake BMC neuroscience Medium 27430330
2019 PICALM interacts with APP via the APP NPXY-motif (interaction abolished by NPXY mutation, shown by co-immunoprecipitation). PTB-domain-containing adaptor proteins Numb, JIP1b, and GULP1 interact with PICALM and enhance the APP-PICALM interaction. Co-expression of distinct PTB-APs differentially alters APP cell surface levels, endocytosis rates, and PICALM nuclear shuttling. Co-immunoprecipitation with APP NPXY-motif mutation, FACS analysis, internalization assays, fluorescence microscopy for nuclear localization The Biochemical journal Medium 31300465
2020 Increased expression of PICALM (or its yeast homolog Yap1802p) rescues APOE4-induced endocytic defects in human iPSC-derived astrocytes, demonstrating a functional interaction between two AD risk factors centered on endocytosis. In yeast, APOE4 expression causes dose-dependent defects in endocytosis and growth that are rescued by Yap1802p overexpression. iPSC-derived human astrocytes (isogenic APOE3/APOE4), yeast model with APOE4 expression, Yap1802p overexpression, endocytosis assays Cell reports Medium 33027662
2020 Picalm haploinsufficiency in Tg30 tau transgenic mice (Tg30xPicalm+/-) significantly aggravates tau pathology: higher pathological tau levels, increased neurofibrillary tangle density, more severe motor deficits, and increased autophagy marker abnormalities compared to Tg30 mice. Transgenic mouse cross (Tg30 x Picalm+/-), behavioral testing, immunohistochemistry for tau pathology, Western blotting for autophagy markers Acta neuropathologica High 31925534
2003 Loss-of-function mutations in the mouse Picalm gene (nonsense/splice-donor mutations causing exon deletions) cause hematopoietic abnormalities, growth retardation, abnormal iron metabolism, and shortened lifespan, establishing PICALM as essential for clathrin-mediated endocytosis-dependent hematopoiesis and iron metabolism in vivo. ENU mutagenesis screen, Sanger sequencing of Picalm mutant alleles, genetic mapping, molecular characterization of splice variants Proceedings of the National Academy of Sciences of the United States of America High 12832620
2021 PICALM disruption (CRISPR/Cas9 exon 1 knockout in HeLa cells) increases numbers of early endosomes, increases abundance of lysosomal enzymes in endosome-enriched fractions, disrupts processing and maturation of cathepsin D, and causes autophagy deficits, establishing PICALM as required for correct maturation of lysosomal enzymes. CRISPR/Cas9 knockout, proteomics of endosome-enriched fractions, Western blotting for cathepsin D processing, immunofluorescence Biochemical and biophysical research communications Medium 34311200
2015 PICALM modulates cellular cholesterol homeostasis: loss of PICALM increases cellular cholesterol pool size (by GC-MS), alters net scavenging of cholesterol, and enhances LDL receptor internalization due to elevated LDLR expression (confirmed by flow cytometry). PICALM influences expression of genes encoding proteins in cholesterol biosynthesis and lipoprotein uptake pathways. Gene expression studies in PICALM-deficient vs expressing cells, GC-MS cholesterol quantification, isotopic labeling studies, flow cytometry for LDLR internalization PloS one Medium 26075887
2020 In Drosophila, increased expression of the PICALM orthologue lap rescues Aβ42 toxicity (glutamatergic neurotransmission defects, survival, behavioral function) without affecting Aβ42 levels. lap modulates presynaptic vesicular glutamate transporter (VGlut) accumulation and spontaneous glutamate release, and modulates the localization of amphiphysin (BIN1 homologue), which in turn affects postsynaptic glutamate receptor localization. Drosophila transgenic model, electrophysiology, behavioral assays, confocal imaging of VGlut and GluRII, genetic interaction with Amph/BIN1 Human molecular genetics Medium 32592479
2023 Artesunate elevates PICALM mRNA and protein levels in endothelial cells and brain capillaries in vivo. In Picalm+/-;5XFAD mice, artesunate increases capillary PICALM levels, reduces Aβ levels and plaque load, and accelerates Aβ clearance from brain to blood. Endothelial-specific PICALM knockout abolishes all beneficial effects, confirming that endothelial PICALM is required for artesunate's therapeutic effects on Aβ pathology. FDA-approved drug screen (2007 compounds, luciferase/PICALM promoter assay), endothelial cell mRNA screen, Picalm+/-;5XFAD mice, Picalmlox/lox;Cdh5-Cre;5XFAD mice, Aβ ELISA, behavioral tests, CBF measurements Molecular neurodegeneration High 36707892
2020 High glucose induces ROS-stimulated Sp1 activation, upregulating PICALM, clathrin heavy chain, and AP2α1, resulting in increased lipid raft-mediated APP endocytosis and early endosomal enlargement that increases Aβ production. PICALM facilitates clathrin-mediated APP endocytosis leading to endosomal enlargement under high glucose conditions. Human neuroblastoma cells under high glucose, siRNA knockdown of PICALM, ROS inhibition, Sp1 inhibition, diabetic mouse model with pharmacological inhibitors, immunofluorescence, Aβ ELISA British journal of pharmacology Medium 32436237
2025 In microglia, the PICALM LOAD-risk allele of rs10792832 reduces PU.1 transcription factor binding and PICALM expression, impairing uptake of Aβ and myelin debris. Reduced PICALM expression in microglia causes lipid droplet (LD) accumulation and phagocytosis deficits. Genetic and pharmacological perturbation established a causal link between reduced PICALM, LD accumulation, and phagocytosis deficits in a microglial-specific manner. Allele-specific open chromatin mapping in iPSC-derived microglia/neurons/astrocytes, genetic PICALM perturbation, pharmacological perturbation, transcriptomic analysis, lipid droplet quantification, phagocytosis assays Nature High 40903578
2024 PICALM is upregulated in cardiomyocytes during doxorubicin-induced cardiotoxicity and promotes Aβ peptide generation, increasing cardiomyocyte membrane permeability. Genetic depletion and pharmacological blocking peptides targeting PICALM reduce Aβ generation and alleviate doxorubicin-induced cardiotoxicity in vitro and in vivo. Single cell/nucleus RNA sequencing, doxorubicin mouse model, genetic Picalm depletion, pharmacological blocking peptides, membrane permeability assays, human heart tissue verification Advanced science Medium 38935046
2024 siRNA-mediated knockdown of Picalm in mature 3T3-L1 adipocytes amplifies insulin-stimulated GLUT4 translocation to the plasma membrane and increases phosphorylation of Akt and Tbc1d4. Picalm depletion before and during differentiation suppresses adipogenesis. Picalm knockdown decreases clathrin-dependent EGF uptake and increases abundance of vesicular trafficking and actin remodeling proteins at the plasma membrane. siRNA knockdown in 3T3-L1 adipocytes and C2C12 myoblasts, GLUT4 translocation assay, insulin signaling (Akt/Tbc1d4 phosphorylation), EGF internalization assay, plasma membrane proteomics Molecular metabolism Medium 39182843
2026 Picalm depletion in C2C12 myoblasts impairs differentiation through diminished intracellular trafficking dynamics, decreased clathrin-dependent EGF uptake, and increased plasma membrane abundance of vesicular trafficking proteins (Vamp3, Vamp5) and actin remodeling proteins (Actn1, Actn4, Rhog, Rock1, Rock2). Pharmacological stabilization of actin filaments with Jasplakinolide rescues myogenic differentiation in Picalm-deficient cells, establishing a functional link between PICALM-dependent endocytosis, actin remodeling, and myogenesis. siRNA knockdown in C2C12 myoblasts and primary myocytes, EGF internalization assay, dynamin inhibition (Dyngo-4a), plasma membrane proteomics, Jasplakinolide rescue, autophagy assays Molecular metabolism Medium 41833602
2024 PICALM knockout by CRISPR-Cas9 screen in CD4+ SupT1 T cells inhibits HIV-1 viral entry and causes defects in intracellular trafficking, increased intracellular Gag accumulation, alterations in autophagy, immune checkpoint PD-1 levels, and differentiation markers, establishing PICALM as a host factor required for HIV-1 entry and intracellular trafficking. CRISPR-Cas9 screen of 140 membrane trafficking proteins, PICALM KO in SupT1 cells, HIV-1 infection assays, flow cytometry, immunofluorescence iScience Medium 38957789
2023 PICALM localizes to both presynaptic active zones and postsynaptic endocytic zones, co-localizes with APP, and forms nanodomains with distinct morphological properties in different subsynaptic regions. Elevated PICALM expression differentially alters lateral diffusion of APP C-terminal deletion mutants, indicating PICALM regulates APP nanoscale dynamics via the APP C-terminal Y682ENPTY687 domain. Single-molecule super-resolution imaging (STORM/PALM), single-particle tracking, APP C-terminal deletion mutants, co-localization analysis in neurons Cellular and molecular life sciences Medium 37726569
2023 PICALM knockdown in uninfected cells increases cholesterol in Golgi and TfR-positive recycling endosomes. In Chlamydia-infected cells, PICALM knockdown increases Golgi-derived lipid/protein, TfR, transferrin, and Rab11-FIP1 localized to chlamydial inclusions and decreases Rab11 trafficking to the inclusion, establishing PICALM as a regulator of cholesterol homeostasis and endosomal recycling pathway trafficking to the chlamydial inclusion. siRNA knockdown of PICALM in infected and uninfected cells, immunofluorescence for cholesterol/Golgi/TfR/Rab11 markers, quantitative imaging Molecular and cellular biology Medium 36779337
2021 SRSF6 regulates alternative splicing of PICALM exon 14, triggering a switch from short to long PICALM isoform (PICALML). CRNDE lncRNA reduces SRSF6 protein stability, thereby affecting this splicing event. Expression of PICALML contributes to autophagy regulation and chemosensitivity in gastric cancer cells. RNA splicing analysis, siRNA knockdown of SRSF6, CRNDE overexpression/knockdown, isoform-specific expression analysis, autophagy flux assays Molecular cancer Medium 33397371

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Central role for PICALM in amyloid-β blood-brain barrier transcytosis and clearance. Nature neuroscience 356 26005850
2014 PICALM modulates autophagy activity and tau accumulation. Nature communications 221 25241929
2013 Adaptor complex AP2/PICALM, through interaction with LC3, targets Alzheimer's APP-CTF for terminal degradation via autophagy. Proceedings of the National Academy of Sciences of the United States of America 201 24067654
2010 Replication of CLU, CR1, and PICALM associations with alzheimer disease. Archives of neurology 178 20554627
2021 LncRNA CRNDE attenuates chemoresistance in gastric cancer via SRSF6-regulated alternative splicing of PICALM. Molecular cancer 156 33397371
2012 Role of phosphatidylinositol clathrin assembly lymphoid-myeloid leukemia (PICALM) in intracellular amyloid precursor protein (APP) processing and amyloid plaque pathogenesis. The Journal of biological chemistry 132 22539346
2013 Clathrin adaptor CALM/PICALM is associated with neurofibrillary tangles and is cleaved in Alzheimer's brains. Acta neuropathologica 118 23589030
2018 The concerted amyloid-beta clearance of LRP1 and ABCB1/P-gp across the blood-brain barrier is linked by PICALM. Brain, behavior, and immunity 117 30041013
2014 The Role of PICALM in Alzheimer's Disease. Molecular neurobiology 93 25186232
2010 Distribution and expression of picalm in Alzheimer disease. Journal of neuropathology and experimental neurology 93 20838239
2022 PICALM and Alzheimer's Disease: An Update and Perspectives. Cells 84 36552756
2013 PICALM gene rs3851179 polymorphism contributes to Alzheimer's disease in an Asian population. Neuromolecular medicine 83 23572399
2020 PICALM Rescues Endocytic Defects Caused by the Alzheimer's Disease Risk Factor APOE4. Cell reports 73 33027662
2012 A yeast model for amyloid-β aggregation exemplifies the role of membrane trafficking and PICALM in cytotoxicity. Disease models & mechanisms 69 22888099
2014 Genetics of PICALM expression and Alzheimer's disease. PloS one 61 24618820
2010 Association of CLU and PICALM variants with Alzheimer's disease. Neurobiology of aging 61 20570404
2010 Genetic variations in the CLU and PICALM genes are associated with cognitive function in the oldest old. Neurobiology of aging 57 20739100
2016 PICALM rs3851179 Variant Confers Susceptibility to Alzheimer's Disease in Chinese Population. Molecular neurobiology 55 27048444
2016 Level of PICALM, a key component of clathrin-mediated endocytosis, is correlated with levels of phosphotau and autophagy-related proteins and is associated with tau inclusions in AD, PSP and Pick disease. Neurobiology of disease 55 27260836
2012 The PICALM protein plays a key role in iron homeostasis and cell proliferation. PloS one 54 22952941
2014 Genotype patterns at CLU, CR1, PICALM and APOE, cognition and Mediterranean diet: the PREDIMED-NAVARRA trial. Genes & nutrition 51 24643340
2003 Mutations in the clathrin-assembly gene Picalm are responsible for the hematopoietic and iron metabolism abnormalities in fit1 mice. Proceedings of the National Academy of Sciences of the United States of America 51 12832620
2016 Decreasing the expression of PICALM reduces endocytosis and the activity of β-secretase: implications for Alzheimer's disease. BMC neuroscience 48 27430330
2012 The clathrin assembly protein PICALM is required for erythroid maturation and transferrin internalization in mice. PloS one 48 22363754
2012 PICALM-MLLT10 acute myeloid leukemia: a French cohort of 18 patients. Leukemia research 45 22871473
2014 The benefits of staying active in old age: physical activity counteracts the negative influence of PICALM, BIN1, and CLU risk alleles on episodic memory functioning. Psychology and aging 40 24660791
2020 Picalm reduction exacerbates tau pathology in a murine tauopathy model. Acta neuropathologica 38 31925534
2014 Role of the clathrin adaptor PICALM in normal hematopoiesis and polycythemia vera pathophysiology. Haematologica 37 25552701
2010 Genetic association of PICALM polymorphisms with Alzheimer's disease in Han Chinese. Journal of the neurological sciences 37 20951388
2020 Lower DNA methylation levels in CpG island shores of CR1, CLU, and PICALM in the blood of Japanese Alzheimer's disease patients. PloS one 35 32991610
2015 Meta-analysis of the Association between Alzheimer Disease and Variants in GAB2, PICALM, and SORL1. Molecular neurobiology 35 26611835
2012 Implication of common and disease specific variants in CLU, CR1, and PICALM. Neurobiology of aging 33 22402018
2010 APP, APOE, complement receptor 1, clusterin and PICALM and their involvement in the herpes simplex life cycle. Neuroscience letters 26 20674675
2011 CLU, CR1 and PICALM genes associate with Alzheimer's-related senile plaques. Alzheimer's research & therapy 25 21466683
2023 Anti-malaria drug artesunate prevents development of amyloid-β pathology in mice by upregulating PICALM at the blood-brain barrier. Molecular neurodegeneration 24 36707892
2014 Genetic evidence for the involvement of variants at APOE, BIN1, CR1, and PICALM loci in risk of late-onset Alzheimer's disease and evaluation for interactions with APOE genotypes. Journal of molecular neuroscience : MN 23 25022885
2010 Acute leukemia with PICALM-MLLT10 fusion gene: diagnostic and treatment struggle. Cancer genetics and cytogenetics 23 20875875
2017 Effect of PICALM rs3851179 polymorphism on the default mode network function in mild cognitive impairment. Behavioural brain research 22 28549650
2017 rs3851179 Polymorphism at 5' to the PICALM Gene is Associated with Alzheimer and Parkinson Diseases in Brazilian Population. Neuromolecular medicine 21 28567584
2019 Exosomal MicroRNA-155 Inhibits Enterovirus A71 Infection by Targeting PICALM. International journal of biological sciences 20 31853228
2025 PICALM Alzheimer's risk allele causes aberrant lipid droplets in microglia. Nature 19 40903578
2020 High glucose-mediated PICALM and mTORC1 modulate processing of amyloid precursor protein via endosomal abnormalities. British journal of pharmacology 19 32436237
2013 Genetic variation in PICALM and Alzheimer's disease risk in Han Chinese. Neurobiology of aging 19 24095218
2021 PICALM mRNA Expression in the Blood of Patients with Neurodegenerative Diseases and Geriatric Depression. Journal of Alzheimer's disease : JAD 18 33386803
2013 Lack of association of CR1, PICALM and CLU gene polymorphisms with Alzheimer disease in a Polish population. Neurologia i neurochirurgia polska 18 23650005
2017 Role of CLU, PICALM, and TNK1 Genotypes in Aging With and Without Alzheimer's Disease. Molecular neurobiology 17 28631188
2016 Inhibition of Aβ42 oligomerization in yeast by a PICALM ortholog and certain FDA approved drugs. Microbial cell (Graz, Austria) 17 28357335
2019 Genetic Variants of PICALM rs541458 Modulate Brain Spontaneous Activity in Older Adults With Amnestic Mild Cognitive Impairment. Frontiers in neurology 16 31133980
2018 PICALM Gene Methylation in Blood of Alzheimer's Disease Patients Is Associated with Cognitive Decline. Journal of Alzheimer's disease : JAD 16 30040717
2012 Identification and confirmation of an exonic splicing enhancer variation in exon 5 of the Alzheimer disease associated PICALM gene. Annals of human genetics 16 22943764
2019 The role of PTB domain containing adaptor proteins on PICALM-mediated APP endocytosis and localization. The Biochemical journal 15 31300465
2016 Effect of CLU and PICALM polymorphisms on AD risk: A study from south India. Asian journal of psychiatry 15 28558900
2014 An intronic PICALM polymorphism, rs588076, is associated with allelic expression of a PICALM isoform. Molecular neurodegeneration 15 25169757
2014 A single codon insertion in PICALM is associated with development of familial subvalvular aortic stenosis in Newfoundland dogs. Human genetics 14 24898977
2011 Implication of a genetic variant at PICALM in Alzheimer’s disease patients and centenarians. Journal of Alzheimer's disease : JAD 14 21297266
2020 PICALM rescues glutamatergic neurotransmission, behavioural function and survival in a Drosophila model of Aβ42 toxicity. Human molecular genetics 13 32592479
2020 Association of Alzheimer's disease risk variants on the PICALM gene with PICALM expression, core biomarkers, and feature neurodegeneration. Aging 13 33170153
2018 A Network of Genetic Effects on Non-Demented Cognitive Aging: Alzheimer's Genetic Risk (CLU + CR1 + PICALM) Intensifies Cognitive Aging Genetic Risk (COMT + BDNF) Selectively for APOEɛ4 Carriers. Journal of Alzheimer's disease : JAD 13 29480189
2016 The impact of PICALM genetic variations on reserve capacity of posterior cingulate in AD continuum. Scientific reports 13 27117083
2016 Quantitative EEG during normal aging: association with the Alzheimer's disease genetic risk variant in PICALM gene. Neurobiology of aging 13 28073596
2015 Modulation of PICALM Levels Perturbs Cellular Cholesterol Homeostasis. PloS one 13 26075887
2022 PICALM exerts a role in promoting CRC progression through ERK/MAPK signaling pathway. Cancer cell international 12 35501863
2017 Associations of polymorphisms in the candidate genes for Alzheimer's disease BIN1, CLU, CR1 and PICALM with gestational diabetes and impaired glucose tolerance. Molecular biology reports 11 28316001
2023 Treatment outcomes of childhood PICALM::MLLT10 acute leukaemias. British journal of haematology 10 37743097
2021 PICALM regulates cathepsin D processing and lysosomal function. Biochemical and biophysical research communications 10 34311200
2019 Association of PICALM Gene Polymorphisms with Alzheimer's Disease: Evidence from an Updated Meta-Analysis. Current Alzheimer research 10 31385771
2018 Mediastinal Myeloid Sarcoma with TP53 Mutation Preceding Acute Myeloid Leukemia with a PICALM-MLLT10 Fusion Gene. Acta haematologica 9 30227397
2024 Alzheimer's disease risk allele of PICALM causes detrimental lipid droplets in microglia. Research square 8 38826437
2020 Genetic Association Between Alzheimer's Disease Risk Variant of the PICALM Gene and EEG Functional Connectivity in Non-demented Adults. Frontiers in neuroscience 8 32372909
2019 Molecular and phenotypic characterization of an early T-cell precursor acute lymphoblastic lymphoma harboring PICALM-MLLT10 fusion with aberrant expression of B-cell antigens. Cancer genetics 7 31739126
2012 Lack of association of the PICALM rs3851179 polymorphism with Parkinson's disease in the Greek population. The International journal of neuroscience 7 22715855
2024 PICALM::MLLT10 may indicate a new subgroup of acute leukemias with miscellaneous immunophenotype and poor initial treatment response but showing sensitivity to venetoclax. EJHaem 6 38895061
2024 Clinicopathologic features and outcomes of acute leukemia harboring PICALM::MLLT10 fusion. Human pathology 6 38971327
2022 PICALM rs3851179 Variants Modulate Left Postcentral Cortex Thickness, CSF Amyloid β42, and Phosphorylated Tau in the Elderly. Brain sciences 6 36552141
2024 miR-155-5p promotes hepatic steatosis via PICALM-mediated autophagy in aging hepatocytes. Archives of gerontology and geriatrics 5 38237377
2024 PICALM Regulating the Generation of Amyloid β-Peptide to Promote Anthracycline-Induced Cardiotoxicity. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 5 38935046
2024 An HIV-1 CRISPR-Cas9 membrane trafficking screen reveals a role for PICALM intersecting endolysosomes and immunity. iScience 5 38957789
2024 Picalm, a novel regulator of GLUT4-trafficking in adipose tissue. Molecular metabolism 5 39182843
2006 Acute monocytic leukemia with coexpression of minor BCR-ABL1 and PICALM-MLLT10 fusion genes along with overexpression of HOXA9. Genes, chromosomes & cancer 5 16518848
2018 Genetic Association between Alzheimer's Disease Risk Variant of the PICALM Gene and Auditory Event-Related Potentials in Aging. Biochemistry. Biokhimiia 4 30472946
2015 LACK OF ASSOCIATIONS BETWEEN CLU AND PICALM GENE POLYMORPHISMS AND ALZHEIMER'S DISEASE IN A TURKISH POPULATION. Ideggyogyaszati szemle 4 26434199
2024 PICALM-MLLT10 fusion gene in hematological neoplasms: clinical features, current practices, and prognoses. Hematology (Amsterdam, Netherlands) 3 39499083
2024 Cholangiocyte-derived exosomal long noncoding RNA PICALM-AU1 promotes pulmonary endothelial cell endothelial-mesenchymal transition in hepatopulmonary syndrome. Heliyon 3 39822730
2023 Real-time heterogeneity of supramolecular assembly of amyloid precursor protein is modulated by an endocytic risk factor PICALM. Cellular and molecular life sciences : CMLS 3 37726569
2024 The Effects of PICALM rs3851179 and Age on Brain Atrophy and Cognition Along the Alzheimer's Disease Continuum. Molecular neurobiology 2 38363532
2023 Eukaryotic Clathrin Adapter Protein and Mediator of Cholesterol Homeostasis, PICALM, Affects Trafficking to the Chlamydial Inclusion. Molecular and cellular biology 2 36779337
2022 Genetic Predictors of Change in Episodic Verbal Memory by Cognitive Intervention: ACT, PICALM, BDNF, NRG1, APOE Genes and Their Interactions in Situations of Cognitive Demand. Journal of integrative neuroscience 2 35864751
2013 Mass spectrometry quantification of PICALM and AP180 in human frontal cortex and neural retina. Analytical biochemistry 2 23954523
2025 MiR- 142 - 3p Up-regulation Mitigates Cerebral Ischemia-reperfusion Injury by Targeting PICALM. Journal of molecular neuroscience : MN 1 40272654
2023 An unusual presentation of a pediatric patient with mixed phenotypic acute leukemia with PICALM::MLLT10 gene rearrangement. Pediatric hematology and oncology 1 37171905
2023 PICALM Variation Moderates the Relationships of APOE ɛ4 with Alzheimer's Disease Cerebrospinal Biomarkers and Memory Function Among Non-Demented Population. Journal of Alzheimer's disease : JAD 1 38007652
2018 Correlation of PICALM polymorphism rs3851179 with Alzheimer's disease among Caucasian and Chinese populations: a meta-analysis and systematic review. Metabolic brain disease 1 30039188
2016 Re: "PICALM Gene rs3851179 Polymorphism Contributes to Alzheimer's Disease in an Asian Population". Neuromolecular medicine 1 26972434
2026 PICALM::MLLT10 translocated leukemia. FEBS letters 0 41532548
2026 Precursor B-Cell Acute Lymphoblastic Leukemia With PICALM∶∶MLLT10 Fusion Gene Positivity:Report of One Case and Literature Review. Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae 0 41565572
2026 PICALM Genetic Variant Alters mRNA Expression Without Affecting Protein Levels or Tau Spreading in Alzheimer's Disease. Cells 0 41677602
2026 Picalm coordinates clathrin-mediated endocytosis and actin remodeling during myogenesis. Molecular metabolism 0 41833602
2026 Microglial PICALM: A novel genetic driver and therapeutic target in vascular dementia. Archives of gerontology and geriatrics 0 42250393
2025 [Diagnostic PICALM::MLLT10 fusion by transcriptome sequencing in acute myeloid leukemia and its clinical characteristics]. Zhonghua nei ke za zhi 0 40050091
2025 Observation of PICALM::MLLT10-rearrangement and coincidental EZH2 mutations in a patient with acute myeloid leukemia: A case report and review of the literature. BJC reports 0 40983660

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