WDPCP (WD Repeat Containing Polypeptide)

WDPCP (WD Repeat Containing Polypeptide)

<div class="infobox infobox-gene">

| Property | Value |
|----------|-------|
| Gene Symbol | WDPCP |
| Full Name | WD Repeat Containing Polypeptide |
| Chromosomal Location | 2p15 |
| NCBI Gene ID | 51026 |
| Ensembl ID | ENSG00000143977 |
| UniProt ID | Q8WZ73 |
| Encoded Protein | WD Repeat Containing Polypeptide |
| Protein Family | WD40 repeat protein family |
| Protein Length | 724 amino acids |
| Molecular Weight | ~79 kDa |
| Associated Diseases | Bardet-Biedl Syndrome, Congenital Heart Disease, Ciliopathies, Autism Spectrum Disorder |

</div>

Overview

WDPCP (WD Repeat Containing Polypeptide) encodes a protein belonging to the WD40 repeat protein family, a large group of regulatory proteins characterized by conserved WD40 repeat motifs that form beta-propeller structures. WDPCP is a critical component of the planar cell polarity (PCP) signaling pathway and plays essential roles in ciliogenesis, autophagy regulation, and cellular morphogenesis[@badgley2015].

The planar cell polarity pathway is a fundamental developmental signaling system that coordinates cell orientation and tissue patterning during embryogenesis. In the central nervous system (CNS), PCP signaling is crucial for neural tube closure, neuronal migration, axonal guidance, and the establishment of brain architecture. WDPCP serves as a key regulator of these processes, and its dysfunction has been implicated in various neurodevelopmental and neurodegenerative conditions.

WDPCP (WD Repeat Containing Polypeptide)

<div class="infobox infobox-gene">

| Property | Value |
|----------|-------|
| Gene Symbol | WDPCP |
| Full Name | WD Repeat Containing Polypeptide |
| Chromosomal Location | 2p15 |
| NCBI Gene ID | 51026 |
| Ensembl ID | ENSG00000143977 |
| UniProt ID | Q8WZ73 |
| Encoded Protein | WD Repeat Containing Polypeptide |
| Protein Family | WD40 repeat protein family |
| Protein Length | 724 amino acids |
| Molecular Weight | ~79 kDa |
| Associated Diseases | Bardet-Biedl Syndrome, Congenital Heart Disease, Ciliopathies, Autism Spectrum Disorder |

</div>

Overview

WDPCP (WD Repeat Containing Polypeptide) encodes a protein belonging to the WD40 repeat protein family, a large group of regulatory proteins characterized by conserved WD40 repeat motifs that form beta-propeller structures. WDPCP is a critical component of the planar cell polarity (PCP) signaling pathway and plays essential roles in ciliogenesis, autophagy regulation, and cellular morphogenesis[@badgley2015].

The planar cell polarity pathway is a fundamental developmental signaling system that coordinates cell orientation and tissue patterning during embryogenesis. In the central nervous system (CNS), PCP signaling is crucial for neural tube closure, neuronal migration, axonal guidance, and the establishment of brain architecture. WDPCP serves as a key regulator of these processes, and its dysfunction has been implicated in various neurodevelopmental and neurodegenerative conditions.

Research over the past decade has established connections between WDPCP and several aspects of neuronal biology relevant to neurodegeneration. These include:

• Regulation of primary cilia formation and function in neurons
• Control of autophagosome biogenesis and autophagy flux
• Participation in neuronal migration during cortical development
• Involvement in axon guidance and neural circuit formation

Gene Structure and Evolution

The WDPCP gene is located on chromosome 2p15, a region that has undergone significant evolutionary conservation. The gene spans approximately 25 kilobases and consists of 14 exons that encode a 724-amino acid protein.

WDPCP is evolutionarily conserved across eukaryotes, with orthologs identified in:

• Mus musculus (mouse) — 96% amino acid identity
• Danio rerio (zebrafish) — 85% identity
• Drosophila melanogaster (fruit fly) — 73% identity
• Caenorhabditis elegans (nematode) — 68% identity

Protein Structure and Function

WD40 Repeat Domain

The WDPCP protein contains six WD40 repeats at its C-terminus, each approximately 44-60 amino acids in length. These repeats form a characteristic beta-propeller structure with six blades, providing a platform for protein-protein interactions. The propeller architecture allows WDPCP to:

• Bind multiple partner proteins simultaneously
• Serve as a scaffolding protein in signaling complexes
• Mediate interactions with membranes and cytoskeletal components

Domain Organization

N-terminal Region (1-200) — Low complexity, regulatory
|
|
Middle Region (200-400) — Proline-rich, SH3-binding motifs
|
|
C-terminal WD40 Domain (400-724) — Six WD40 repeats, protein interactions

The N-terminal region contains low-complexity sequences that may undergo regulatory modifications. The middle region includes proline-rich sequences that potentially interact with SH3 domain-containing proteins. The C-terminal WD40 domain mediates the majority of protein-protein interactions.

Role in Planar Cell Polarity

PCP Signaling Overview

The planar cell polarity (PCP) pathway is one of two major Wht signaling pathways (the other being the canonical Wnt/β-catenin pathway). PCP signaling controls the orientation of cells within the plane of a tissue, coordinating collective cell movements and establishing tissue polarity.

Key PCP components include:

• Frizzled receptors (Fzd1-10) — Wnt receptors
• Dishevelled (Dvl) — Cytoplasmic scaffold
• Van Gogh (Vangl) proteins (Vangl1, Vangl2) — Core PCP components
• Prickle (Pk) — Intracellular regulator
• WDPCP — Peripheral membrane protein
• Celsr (Celsr1-3) — Adhesion receptor

WDPCP in PCP Signaling

WDPCP localizes to the plasma membrane and centrosome/basal body, positioning it to coordinate PCP signaling with cellular architecture. Studies demonstrate that WDPCP:

The planar cell polarity pathway is essential for:

• Neural tube closure during embryogenesis
• Neuronal migration in the developing cortex
• Axon guidance and neural circuit formation
• Ciliary positioning and function

Role in Ciliogenesis

Primary Cilia Overview

Primary cilia are antenna-like organelles that project from the cell surface and serve as critical signaling hubs. They detect mechanical and chemical signals from the environment and coordinate intracellular signaling pathways, including:

• Hedgehog signaling
• Wnt signaling (both canonical and non-canonical/PCP)
• PDGF signaling
• Mechanical sensing

• Neurotransmitter receptor localization
• Signaling pathway modulation
• Cell cycle regulation
• Ciliary membrane protein trafficking

WDPCP and Ciliary Assembly

WDPCP is essential for primary cilia formation through its role in basal body docking and ciliary membrane trafficking[@kim2010]. Research demonstrates that:

The ciliogenesis function of WDPCP is particularly important because primary cilia serve as organizing centers for multiple signaling pathways relevant to neurodevelopment and neurodegeneration.

Ciliopathies and Neurodevelopmental Disorders

WDPCP mutations cause or contribute to ciliopathies, a group of disorders characterized by ciliary dysfunction. The Bardet-Biedl syndrome (BBS) phenotype in particular involves:

• Retinal degeneration
• Obesity
• Polydactyly
• Renal anomalies
• Learning disabilities

• Cognitive impairment
• Behavioral disorders
• Developmental delay
• Autism spectrum features

Role in Autophagy

Autophagy Overview

Autophagy (macroautophagy) is a cellular recycling process that degrades damaged organelles, protein aggregates, and intracellular pathogens. Autophagy is essential for cellular homeostasis and is particularly important in neurons due to their post-mitotic nature and high metabolic demands.

The autophagy process involves:

WDPCP in Autophagosome Formation

Research by Badgley et al. (2015) established WDPCP as a regulator of autophagosome formation[@badgley2015]. The mechanism involves:

Implications for Neurodegeneration

Autophagy dysfunction is a central feature of neurodegenerative diseases:

• Alzheimer's disease: Impaired autophagic flux leads to accumulation of autophagic vacuoles containing Aβ and damaged organelles
• Parkinson's disease: Dysfunctional autophagy contributes to α-synuclein aggregation and dopaminergic neuron death
• Huntington's disease: Mutant huntingtin disrupts autophagy machinery
• Amyotrophic lateral sclerosis (ALS): Autophagy defects accelerate motor neuron degeneration

• Protein aggregates (Aβ, α-synuclein, TDP-43)
• Damaged mitochondria (mitophagy)
• Lipid droplets
• Pathogens

Expression Patterns

Tissue Distribution

WDPCP is expressed in multiple tissues, with particularly high expression in:

| Tissue | Expression Level |
|--------|-----------------|
| Brain | High (cortex, hippocampus, cerebellum) |
| Kidney | High |
| Heart | Moderate |
| Lung | Moderate |
| Retina | High |
| Testis | High |

CNS Expression

Within the brain, WDPCP shows cell-type-specific expression:

• Neurons: High expression in pyramidal neurons of cortex and hippocampus
• Astrocytes: Moderate expression
• Oligodendrocytes: Lower expression
• Microglia: Very low expression

• Cortical neurogenesis (embryonic day 14-18 in mouse)
• Neuronal migration periods
• Axon guidance and circuit formation phases

Disease Associations

Neurodegenerative Disease Connections

Alzheimer's Disease

WDPCP has been implicated in Alzheimer's disease through multiple mechanisms:

Gene-wide association studies (GWAS) have identified WDPCP variants as potential modifiers of AD risk, though the relationship requires further validation.

Parkinson's Disease

In Parkinson's disease, WDPCP connections include:

Other Neurodegenerative Conditions

• Huntington's disease: Autophagy regulation by WDPCP may affect mutant huntingtin clearance
• Amyotrophic lateral sclerosis: Ciliary dysfunction may contribute to motor neuron degeneration
• Spinocerebellar ataxia: PCP and ciliary pathways may be affected

Neurodevelopmental Disorders

WDPCP mutations are associated with:

Signaling Pathways

Therapeutic Implications

Target Opportunities

The multifaceted roles of WDPCP in neurodegeneration suggest several therapeutic approaches:

Challenges

• WDPCP has multiple cellular functions, making selective targeting difficult
• The WD40 repeat proteins often have pleiotropic effects
• Delivery to the CNS requires overcoming the blood-brain barrier

Interactions and Partners

Protein-Protein Interactions

WDPCP interacts with several key proteins:

| Partner | Function | Interaction Type |
|---------|----------|-----------------|
| Vangl1/2 | PCP signaling | Direct binding |
| Dvl | Wnt/PCP signaling | Scaffold |
| Atg proteins | Autophagy | Regulatory |
| Basal body proteins | Ciliogenesis | Localization |
| Lipid membranes | Membrane association | Lipid binding |

Signaling Network Integration

WDPCP serves as a signaling hub that integrates multiple pathways:

• Wnt/PCP → WDPCP → cellular morphogenesis
• Autophagy machinery → WDPCP → lysosomal degradation
• Ciliary signaling → WDPCP → hedgehog/wnt pathways

See Also

• [Planar Cell Polarity Pathway](/mechanisms/planar-cell-polarity) — PCP signaling overview
• [Primary Cilia in Neurons](/cell-types/neurons) — Ciliary function in CNS
• [Autophagy in Neurodegeneration](/mechanisms/autophagy) — Autophagy and disease
• [Alzheimer's Disease](/diseases/alzheimers-disease) — AD context
• [Parkinson's Disease](/diseases/parkinsons-disease) — PD context
• [Ciliopathies](/diseases/ciliopathies) — Ciliary disorder spectrum

External Links

• [NCBI Gene: 51026](https://www.ncbi.nlm.nih.gov/gene/51026)
• [Ensembl: ENSG00000143977](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000143977)
• [UniProt: Q8WZ73](https://www.uniprot.org/uniprot/Q8WZ73)
• [GeneCards: WDPCP](https://www.genecards.org/cgi-bin/carddisp.pl?gene=WDPCP)
• [Allen Brain Atlas: WDPCP Expression](https://human.brain-map.org/microarray/search/show?search_term=WDPCP)

References