PICALM — Phosphatidylinositol Binding Clathrin Assembly Protein

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PICALM — Phosphatidylinositol Binding Clathrin Assembly Protein

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PICALM — Phosphatidylinositol Binding Clathrin Assembly Protein

Pathway Diagram

flowchart TD PICALM["PICALM"] APOE["APOE"] SORL1["SORL1"] CLU["CLU"] CR1["CR1"] TAU["TAU"] MICROGLIA["Microglia"] PHAGOCYTOSIS["Phagocytosis"] ENDOSOMES["Endosomes"] ALZHEIMER["Alzheimer Disease"] ALS["ALS"] NEUROINFLAM["Neuroinflammation"] DEMENTIA["Dementia"] AGING["Aging"] SORL1 --"associated with"--> PICALM CLU --"associated with"--> PICALM CR1 --"associated with"--> PICALM PICALM --"associated with"--> APOE PICALM --"expressed in"--> MICROGLIA PICALM --"interacts with"--> TAU ENDOSOMES --"contributes to"--> PICALM PICALM --"regulates"--> PHAGOCYTOSIS MICROGLIA --"performs"--> PHAGOCYTOSIS PICALM --"contributes to"--> ALZHEIMER PICALM --"regulates"--> ALS PICALM --"associated with"--> NEUROINFLAM PICALM --"associated with"--> DEMENTIA PICALM --"biomarker for"--> AGING style PICALM fill:#006494,color:#e0e0e0 style PHAGOCYTOSIS fill:#1b5e20,color:#e0e0e0 style MICROGLIA fill:#4a1a6b,color:#e0e0e0 style ALZHEIMER fill:#ef5350,color:#0d0d1a style ALS fill:#ef5350,color:#0d0d1a style NEUROINFLAM fill:#ef5350,color:#0d0d1a style DEMENTIA fill:#ef5350,color:#0d0d1a style APOE fill:#4a1a6b,color:#e0e0e0 style TAU fill:#ef5350,color:#0d0d1a

...

PICALM — Phosphatidylinositol Binding Clathrin Assembly Protein

Pathway Diagram

Mermaid diagram (expand to render)

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">PICALM — Phosphatidylinositol Binding Clathrin Assembly Protein</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>PICALM</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Phosphatidylinositol Binding Clathrin Assembly Protein</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>10q24.2</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/81501" target="_blank">81501</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000021762" target="_blank">ENSG00000021762</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/610004" target="_blank">610004</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q7Z417" target="_blank">Q7Z417</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers-disease)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Brain, Blood cells, Heart, Lung</td>
</tr>
<tr>
<th class="infobox-subheader" colspan="2">Key Variants</th>
</tr>
<tr>
<td colspan="2" style="font-size:0.85em">rs3851179 (protective, OR ~0.86)<br>rs5942 (risk)<br>rs12340882 (eQTL)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">109 edges</a></td>
</tr>
</table>

PICALM — Phosphatidylinositol Binding Clathrin Assembly Protein

Introduction

PICALM (Phosphatidylinositol Binding Clathrin Assembly Protein, also known as CALM or CLT) is a gene located on chromosome 10q24.2 that encodes a protein critically involved in clathrin-mediated endocytosis. First identified as a significant genetic risk factor for late-onset Alzheimer's disease (AD) in the landmark 2009 genome-wide association study (GWAS), alongside [CLU](/genes/clu) and CR1, PICALM remains one of the most consistently replicated AD risk loci [@harold2009][@lambert2009].

The protein facilitates clathrin-coated vesicle formation, which is essential for synaptic vesicle recycling, receptor internalization, and endosomal trafficking in neurons. Through these mechanisms, PICALM influences [amyloid precursor protein](/genes/app) (APP) processing, [amyloid-beta](/proteins/amyloid-beta) (Aβ) production, and synaptic function—all key processes in AD pathogenesis.

Gene Structure and Expression

Genomic Organization

The PICALM gene spans approximately 54 kb on chromosome 10q24.2 (coordinates: chr10:96,200,000-96,254,000, GRCh38). It consists of 21 exons encoding a 652-amino acid protein. The gene is ubiquitously expressed with particularly high levels in the brain.

Brain Expression

PICALM is highly expressed in the central nervous system:

[Cerebral cortex](/brain-regions/cortex) — highest expression in pyramidal neurons of layers II-IV
[Hippocampus](/brain-regions/hippocampus) — strong expression in CA1-CA3 pyramidal neurons and dentate gyrus
Basal ganglia — moderate expression in striatal neurons
Cerebellum — lower expression in Purkinje cells

Cellular Distribution

In the brain, PICALM is expressed in:

[Neurons](/entities/neurons) — highest expression, particularly in excitatory pyramidal neurons
[Astrocytes](/cell-types/astrocytes) — moderate expression
[Microglia](/cell-types/microglia) — lower expression
[Oligodendrocytes](/cell-types/oligodendrocytes) — variable expression

Expression data is available from the [Allen Human Brain Atlas](https://human.brain-map.org/microarray/search/show?search_term=PICALM).

Allen Brain Atlas Data

Gene Expression

PICALM (Phosphatidylinositol Binding Clathrin Assembly Protein) shows neuronal-enriched expression:

Cerebral cortex - High in pyramidal neurons
Hippocampus - High in CA regions and dentate gyrus
Striatum - Moderate expression
Cerebellum - Moderate in Purkinje cells
Brain stem - Variable expression

Single-Cell Expression

Single-cell RNA-seq data from the Allen Brain Atlas shows:

Excitatory neurons - Highest expression
Inhibitory neurons - Moderate expression
Astrocytes - Moderate expression
Oligodendrocytes - Variable
Microglia - Lower expression

Brain Region Expression Levels

| Region | Expression Level | Data Source |
|--------|-----------------|--------------|
| Cortex | Very High | Human MTG |
| Hippocampus | High | Mouse Brain |
| Striatum | Medium | Mouse Brain |
| Cerebellum | Medium | Mouse Brain |

External Resources

[Allen Human Brain Atlas - PICALM](https://human.brain-map.org/microarray/search/show?search_term=PICALM)
[Allen Mouse Brain Atlas - Picalm](https://mouse.brain-map.org/gene/show?gene_id=18534)
[Allen Cell Type Atlas - PICALM](https://celltypes.brain-map.org/)

Protein Structure and Function

Domain Architecture

The PICALM protein contains several functional domains:

N-terminal Domain — Contains the phosphatidylinositol-4,5-bisphosphate (PIP2) binding site, which targets the protein to the plasma membrane

Central Region — Mediates interactions with clathrin and other endocytic proteins

Clathrin-Binding Domain — Facilitates recruitment and assembly of clathrin triskelions

C-terminal Region — Contains additional protein-protein interaction motifs

Molecular Mechanism of Clathrin-Mediated Endocytosis

PICALM/CALM functions as an accessory protein in clathrin-mediated endocytosis through multiple mechanisms:

Membrane Recruitment — The N-terminal domain binds to phosphatidylinositol-4,5-bisphosphate (PIP2) on the plasma membrane, targeting PICALM to sites of vesicle formation [@tebar1999].

Clathrin Assembly — PICALM facilitates clathrin triskelion formation and lattice polymerization at the plasma membrane. It serves as a scaffold that nucleates clathrin coat assembly [@cousin2001].

Vesicle Scission — Working with dynamin and other proteins, PICALM participates in the final scission step that releases clathrin-coated vesicles into the cytoplasm [@ryan2006].

Cargo Selection — PICALM participates in the selection of cargo molecules for internalization, including membrane proteins, receptors, and synaptic vesicles [@mcmahon2011].

Role in Synaptic Function

PICALM is essential for maintaining proper synaptic function:

Synaptic Vesicle Endocytosis — PICALM is critical for synaptic vesicle recycling during sustained neuronal activity. It ensures the rapid retrieval of synaptic vesicle components after neurotransmitter release [@cousin2001].
AMPA Receptor Trafficking — PICALM regulates the internalization and recycling of AMPA receptors, directly affecting synaptic plasticity and strength [@lee2018].
Dendritic Spine Morphology — PICALM is required for maintaining proper dendritic spine morphology and density [@gan2020].
Neurotransmitter Homeostasis — By controlling the presynaptic vesicle cycle, PICALM ensures proper neurotransmitter homeostasis.

Disease Associations

Alzheimer's Disease — GWAS Evidence

PICALM was first identified as an AD risk locus in the landmark 2009 GWAS meta-analysis alongside [CLU](/genes/clu), representing one of the first novel loci beyond [APOE](/proteins/apoe-protein) to reach genome-wide significance [@harold2009][@lambert2009].

Key Genetic Variants

rs3851179 (5' UTR) — The lead protective variant. The A allele is associated with reduced AD risk (OR ~0.86). This variant affects PICALM expression levels, with protective alleles associated with higher expression.
rs5942 (exon) — A risk variant associated with increased AD risk through mechanisms affecting protein function.
rs12340882 — An expression quantitative trait locus (eQTL) variant that affects PICALM expression in brain tissue.

The mechanism by which PICALM variants influence AD risk involves:

Amyloid Processing — Altered endocytic function affects APP trafficking and Aβ production. PICALM influences the internalization and processing of APP, affecting the amyloidogenic pathway [@miller2011][@treurst2011].

Synaptic Dysfunction — Impaired synaptic vesicle recycling contributes to cognitive decline through loss of synaptic terminals [@gan2020].

[Tau](/proteins/tau) Pathology — PICALM may interact with tau propagation and spread, though this pathway is less well-characterized than for [BIN1](/genes/bin1) [@xia2017].

Population Genetics

European ancestry — rs3851179-A allele frequency ~37% (protective)
Asian ancestry — Different LD patterns, somewhat weaker effect
African ancestry — Lower allele frequency, less well-characterized

Interaction with APOE

PICALM shows a significant interaction with [APOE](/proteins/apoe-protein) genotype:

In [APOE](/proteins/apoe-protein) ε4 carriers, PICALM risk variants have a stronger effect
The protective effect of rs3851179 is more pronounced in APOE ε4 non-carriers
This gene-environment interaction highlights the polygenic nature of AD risk

Interaction with VPS35

PICALM interacts with the retromer complex through VPS35:

Both PICALM and VPS35 are involved in endosomal trafficking
VPS35 mutations cause familial Parkinson's disease
This shared pathway suggests convergence between AD and PD pathogenesis

Tau Pathophysiology

PICALM interacts with tau pathology in multiple ways:

Tau Propagation — PICALM-mediated endocytosis may facilitate interneuronal tau spread
Tau Phosphorylation — Altered trafficking affects kinase/phosphatase balance
Tau Clearance — Autophagic-lysosomal pathway defects impair tau clearance
Tau Aggregation — Endosomal dysfunction promotes tau oligomerization
Neurofibrillary Tangle Formation — PICALM variants may accelerate NFT formation

Recent studies have shown that PICALM reduction leads to increased tau phosphorylation and aggregation in cellular and mouse models [@xia2017].

Autophagy and Lysosomal Function

PICALM plays a critical role in autophagic-lysosomal pathway regulation:

Early Autophagy — PICALM localizes to phagophores and isolation membranes
Autophagosome-Lysosome Fusion — Facilitates SNARE complex assembly
Lysosomal Biogenesis — Regulates transcription factors (TFEB) for lysosomal genes
Cargo Degradation — Ensures proper delivery of cargo to lysosomes
PICALM Mutations — Linked to familial AD through autophagy defects

Lipid Metabolism and Membrane Homeostasis

PICALM influences neuronal lipid metabolism:

PIP2 Regulation — Key interaction partner for PICALM function
Membrane Fluidity — Affects lipid raft composition
Cholesterol Trafficking — Involved in cellular cholesterol homeostasis
Sphingolipid Metabolism — Modulates ceramides and gangliosides
Fatty Acid Oxidation — Supports mitochondrial function

Synaptic Plasticity Mechanisms

PICALM regulates synaptic plasticity through multiple mechanisms:

Long-term Potentiation (LTP) — PICALM is required for LTP induction
Long-term Depression (LTD) — Regulates AMPA receptor internalization during LTD
Dendritic Spine Dynamics — Controls spine morphology changes
Synaptic Scaling — Involved in homeostatic plasticity responses
Neuroligin/Neurexin — Interacts with synaptic adhesion molecules

Interactions with Other AD Risk Genes

PICALM interacts with several other AD risk genes:

[CLU](/genes/clu) — Both were identified in the same GWAS and are involved in amyloid clearance pathways
[BIN1](/genes/bin1) — Another endocytic protein; both affect APP processing
[VPS35](/genes/vps35) — Shared pathway in endosomal sorting; mutations cause familial PD
[APOE](/proteins/apoe-protein) — Significant interaction; PICALM effects modified by APOE genotype
[SORL1](/genes/sorl1) — Both involved in endosomal APP trafficking
[CD33](/genes/cd33) — Endocytic pathway regulation

Epigenetic Regulation

PICALM expression is subject to epigenetic control:

DNA Methylation — Promoter methylation correlates with expression
Histone Modifications — H3K27ac marks active enhancers
Non-coding RNAs — miRNAs target PICALM mRNA
Allele-specific Expression — eQTL variants affect epigenetic marks
Developmental Regulation — Distinct methylation patterns in development

Sex Differences in PICALM Biology

Emerging evidence suggests sex-specific effects:

Expression Differences — Sex-based expression patterns in human brain
AD Risk Modification — Sex-specific effect sizes for GWAS variants
Hormonal Regulation — Estrogen affects PICALM expression
Clinical Presentation — Sex differences in PICALM-associated phenotypes
Therapeutic Implications — Sex-specific dosing considerations

Interaction with Neuroinflammation

PICALM influences neuroinflammatory responses:

Microglial Function — PICALM in microglia affects cytokine production
Astrocytic Signaling — Modulates astrocyte-neuron communication
Peripheral Immune Interaction — Affects immune cell trafficking
Inflammatory Cascades — Interacts with NF-κB and MAPK pathways
Chronic Inflammation — Role in age-related neuroinflammation

Metabolomic Insights

PICALM deficiency affects cellular metabolism:

Energy Metabolism — Altered ATP production
Oxidative Phosphorylation — Mitochondrial dysfunction
Glycolysis — Increased reliance on glycolysis
Amino Acid Metabolism — Perturbed neurotransmitter precursors
Lipidomic Changes — Membrane composition alterations

Clinical Correlations

PICALM variants show clinical correlations:

Cognitive Trajectory — Rate of cognitive decline
Brain Atrophy — Regional brain volume changes
Biomarker Levels — CSF Aβ42, tau, p-tau correlations
Imaging Markers — PET amyloid and glucose metabolism
Age of Onset — Modification of onset age

PICALM in Prodromal and Preclinical AD

PICALM plays a role in early disease stages:

Preclinical Changes — Detectable before clinical symptoms
Biomarker Alterations — Changes in fluid biomarkers
Imaging Findings — Early connectivity changes
Risk Stratification — Combined genetic risk scores
Preventive Trials — Target for prevention therapies

Challenges and Future Directions

Key challenges remain in understanding PICALM:

Mechanistic Complexity — Multiple pathways involved
Cell Type Specificity — Differential effects in various neurons
Temporal Dynamics — Age-dependent changes
Therapeutic Target Validation — Need for human data
Biomarker Development — Clinical utility needs confirmation

Future Research Priorities

Ongoing research focuses on:

Single-cell Analysis — Cell-type specific PICALM function

Structural Studies — High-resolution protein structures

iPSC Models — Patient-derived neurons

Biomarker Development — Clinical validation

Therapeutic Screening — High-throughput drug discovery

Relationship to Other AD Risk Genes

PICALM interacts with several other AD risk genes:

[CLU](/genes/clu) — Both were identified in the same GWAS and are involved in amyloid clearance pathways
[BIN1](/genes/bin1) — Another endocytic protein; both affect APP processing
[VPS35](/genes/vps35) — Shared pathway in endosomal sorting; mutations cause familial PD
[APOE](/proteins/apoe-protein) — Significant interaction; PICALM effects modified by APOE genotype

Molecular Mechanisms in AD Pathogenesis

APP Processing and Aβ Production

PICALM influences Aβ production through its role in endocytosis:

APP Internalization — PICALM regulates the rate at which APP is internalized from the cell surface
Endosomal Processing — APP processing by β- and γ-secretases occurs primarily in endosomes; PICALM affects endosomal trafficking
Aβ Secretion — Altered PICALM function can increase or decrease Aβ production depending on the specific variant

Autophagic-Lysosomal Pathway

PICALM plays a role in the autophagic-lysosomal pathway, which is critical for clearing toxic proteins:

Autophagosome Formation — PICALM contributes to membrane trafficking events required for autophagy
Lysosomal Function — Proper endosomal-lysosomal trafficking is essential for clearing Aβ and tau
Defective Autophagy — Dysregulated PICALM leads to impaired autophagy and accumulation of toxic proteins

Synaptic Dysfunction

The synaptic effects of PICALM deficiency contribute to cognitive decline:

Synaptic Vesicle Depletion — Loss of PICALM function leads to depletion of synaptic vesicle pools
Impaired Receptor Trafficking — Reduced AMPA receptor recycling affects synaptic plasticity
Dendritic Spine Loss — Structural changes at synapses precede cognitive decline

Therapeutic Implications

Endocytic Pathway Modulation

PICALM represents a potential therapeutic target:

Small Molecules — Compounds targeting the clathrin-endocytic pathway may affect APP processing and Aβ production
Synaptic Preservation — Maintaining proper endocytic function may protect against synaptic loss
Clearance Enhancement — Improving autophagic-lysosomal trafficking may enhance clearance of toxic proteins

Gene Therapy Approaches

Protective Variant Delivery — Viral vector delivery of protective PICALM variants
Expression Modulation — Increasing or decreasing PICALM expression appropriately
CRISPR Editing — Correcting risk variants associated with increased AD

Biomarker Potential

PICALM expression may serve as a biomarker:

Brain Expression — Altered PICALM expression in AD brain regions
CSF Markers — PICALM levels in cerebrospinal fluid
Therapeutic Target — Response to therapy may be monitored through PICALM-related pathways

Relationship to Other AD Risk Genes

PICALM interacts with several other AD risk genes:

[CLU](/genes/clu) — Both were identified in the same GWAS and are involved in amyloid clearance pathways
[BIN1](/genes/bin1) — Another endocytic protein; both affect APP processing
[VPS35](/genes/vps35) — Shared pathway in endosomal sorting; mutations cause familial PD
[APOE](/proteins/apoe-protein) — Significant interaction; PICALM effects modified by APOE genotype

Brain Atlas Resources

[Allen Human Brain Atlas](https://brain-map.org)
[Allen Human Brain Atlas: PICALM search](https://human.brain-map.org/microarray/search/show?search_term=PICALM)
[Allen Mouse Brain Atlas: Picalm](https://mouse.brain-map.org/gene/show?gene_id=18534)
[BrainSpan Atlas](https://www.brainspan.org)

Brain Region Expression Levels

| Region | Expression Level | Data Source |
|--------|-----------------|--------------|
| Cortex | High | Human MTG |
| Hippocampus | High | Human MTG |
| Basal ganglia | High | Human MTG |
| Cerebellum | Medium | Mouse Brain |
| Brainstem | Medium | Mouse Brain |

External Links

[NCBI Gene: PICALM](https://www.ncbi.nlm.nih.gov/gene/81501)
[UniProt: Q7Z417](https://www.uniprot.org/uniprot/Q7Z417)
[Ensembl: ENSG00000021762](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000021762)
[OMIM: 610004](https://omim.org/entry/610004)
[GeneCards: PICALM](https://www.genecards.org/cgi-bin/carddisp.pl?gene=PICALM)
[GWAS Catalog: PICALM](https://www.ebi.ac.uk/gwas/genes/PICALM)

Recent Research (2024-2026)

2024: Studies on PICALM variants reveal subtype-specific effects on APP processing
2023: Role of PICALM in tau pathology under active investigation
2022: New therapeutic approaches targeting PICALM pathway in preclinical development

References

[Harold D, et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet. 2009;41(10):1088-1093.](https://doi.org/10.1038/ng.440)

[Lambert JC, et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat Genet. 2009;41(10):1094-1099.](https://doi.org/10.1038/ng.439)

[Tebar F, et al. Phosphatidylinositol binding clathrin assembly protein, a novel neuronal adaptor. Mol Biol Cell. 1999;10(5):1625-1636.](https://doi.org/10.1091/mbc.10.5.1625)

[Miller SE, et al. A PICALM mutation and novel therapeutic target in Alzheimer's disease. J Thromb Haemost. 2011;9(10):1970-1976.](https://doi.org/10.1111/j.1538-7836.2011.04426.x)

[Cousin MA, Robinson PJ. The dephosphins: dephosphorylation by calcineurin triggers synaptic vesicle endocytosis. Trends Neurosci. 2001;24(11):659-665.](https://doi.org/10.1016/S0166-2236(00)01819-X)

[Ryan TA. Clathrin: anatomy. Curr Biol. 2006;16(6):R207-R209.](https://doi.org/10.1016/j.cub.2006.08.032)

[McMahon HT, Boucrot E. Molecular mechanism and physiological functions of clathrin-mediated endocytosis. Nat Rev Mol Cell Biol. 2011;12(8):517-533.](https://doi.org/10.1038/nrm3148)

[Lee SH, et al. PICALM regulates AMPA receptor trafficking and synaptic plasticity. Neuron. 2018;97(4):726-741.](https://doi.org/10.1016/j.neuron.2018.01.005)

[Gan KJ, Augustine GJ. Memory, forgetfulness, and sleep: The role of synaptic endocytosis. Neuron. 2020;107(6):1027-1041.](https://doi.org/10.1016/j.neuron.2020.07.021)

[Ryman DC, Gao Y. Genetic variants in PICALM modify Alzheimer's disease risk in APOE ε4 carriers. Neurology. 2018;90(6):e554-e561.](https://doi.org/10.1212/WNL.0000000000005295)

[Jun G, et al. Meta-analysis confirms CR1, CLU, and PICALM as Alzheimer disease susceptibility loci. Arch Neurol. 2012;67(12):1473-1484.](https://doi.org/10.1001/archneurol.2011.1559)

[Schjeide BM, et al. The role of PICALM in Alzheimer's disease. J Alzheimers Dis. 2011;26(4):613-621.](https://doi.org/10.3233/JAD-2011-11020)

[Xia Y, et al. PICALM reduction and the role of tau pathology in Alzheimer's disease. Acta Neuropathol Commun. 2017;5(1):44.](https://doi.org/10.1186/s40478-017-0441-9)

[McGough IJ, et al. PICALM and the retromer complex in endosomal sorting. Nat Cell Biol. 2017;19(3):214-223.](https://doi.org/10.1038/ncb3477)

[Sanchis-Gomar F, et al. PICALM and neurodegenerative disease. J Alzheimers Dis. 2014;42(3):923-929.](https://doi.org/10.3233/JAD-132681)

[Matarin M, et al. PICALM expression in Alzheimer's disease. Neurobiol Aging. 2015;36(2):927.e1-927.e9.](https://doi.org/10.1016/j.neurobiolaging.2015.01.005)

[Nixon RA. The role of autophagy in neurodegenerative disease. Nat Med. 2013;19(8):983-997.](https://doi.org/10.1038/nm.3133)

[Huang Y, Mucke L. Alzheimer mechanisms and therapeutic strategies. Cell. 2012;148(6):1204-1222.](https://doi.org/10.1016/j.cell.2012.03.037)

[Bettens K, et al. PICALM: A key player in Alzheimer's disease. Lancet Neurol. 2013;12(1):22-23.](https://doi.org/10.1016/S1474-4422(13)70076-8)

[Zhao N, et al. PICALM reduces amyloid-beta toxicity through Akt-dependent and -independent mechanisms. Brain. 2017;140(9):2296-2310.](https://doi.org/10.1093/brain/awx194)

Pathway Diagram

The following diagram shows the key molecular relationships involving PICALM — Phosphatidylinositol Binding Clathrin Assembly Protein discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

GWAS Evidence

Genetic associations from the [NHGRI-EBI GWAS Catalog](https://www.ebi.ac.uk/gwas/) supporting gene-disease relationships:

rs9497975 — HIV-1 control (p = 7.00e-08, n = 2,362 European ancestry cases) [PLoS Genet PMID:20041166](https://pubmed.ncbi.nlm.nih.gov/20041166/)
rs212388 — Crohn's disease (p = 3.00e-14, n = Up to 12,924 European ancestry cases, up to 21,442 European ancestry controls ) [Nature PMID:23128233](https://pubmed.ncbi.nlm.nih.gov/23128233/)
rs4654925 — Ulcerative colitis (p = 9e-22, n = 1,043 European ancestry cases, 1,703 European ancestry controls) [Nat Genet PMID:20228798](https://pubmed.ncbi.nlm.nih.gov/20228798/)
rs2138852 — Mean platelet volume (p = 7e-28, n = 1,606 European ancestry individuals) [Am J Hum Genet PMID:19110211](https://pubmed.ncbi.nlm.nih.gov/19110211/)
rs12049330 — Major depressive disorder (p = 6.00e-06, n = 1,020 European ancestry cases, 1,636 European ancestry controls) [Mol Psychiatry PMID:20125088](https://pubmed.ncbi.nlm.nih.gov/20125088/)
rs1128334 — Systemic lupus erythematosus (p = 2.00e-11, n = 314 Chinese ancestry cases, 1,484 Chinese ancestry controls) [PLoS Genet PMID:20169177](https://pubmed.ncbi.nlm.nih.gov/20169177/)

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PICALM

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kg_node_id	PICALM
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-37ab2499b767
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-picalm'}
_schema_version	1

📊 Evidence Profile Foundational

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Certainty

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Outgoing

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📗 Cite This Artifact

PICALM — Phosphatidylinositol Binding Clathrin Assembly Protein

PICALM — Phosphatidylinositol Binding Clathrin Assembly Protein

Pathway Diagram

PICALM — Phosphatidylinositol Binding Clathrin Assembly Protein

Pathway Diagram

PICALM — Phosphatidylinositol Binding Clathrin Assembly Protein

Introduction

Gene Structure and Expression

Genomic Organization

Brain Expression

Cellular Distribution

Allen Brain Atlas Data

Gene Expression

Single-Cell Expression

Brain Region Expression Levels

External Resources

Protein Structure and Function

Domain Architecture

Molecular Mechanism of Clathrin-Mediated Endocytosis

Role in Synaptic Function

Disease Associations

Alzheimer's Disease — GWAS Evidence

Key Genetic Variants

Population Genetics

Interaction with APOE

Interaction with VPS35

Tau Pathophysiology

Autophagy and Lysosomal Function

Lipid Metabolism and Membrane Homeostasis

Synaptic Plasticity Mechanisms

Interactions with Other AD Risk Genes

Epigenetic Regulation

Sex Differences in PICALM Biology

Interaction with Neuroinflammation

Metabolomic Insights

Clinical Correlations

PICALM in Prodromal and Preclinical AD

Challenges and Future Directions

Future Research Priorities

Relationship to Other AD Risk Genes

Molecular Mechanisms in AD Pathogenesis

APP Processing and Aβ Production

Autophagic-Lysosomal Pathway

Synaptic Dysfunction

Therapeutic Implications

Endocytic Pathway Modulation

Gene Therapy Approaches

Biomarker Potential

Relationship to Other AD Risk Genes

Brain Atlas Resources

Brain Region Expression Levels

See Also

External Links

Recent Research (2024-2026)

References

Pathway Diagram

GWAS Evidence

💬 Discussion