WDR41 Gene

Migration, Crosslink

📖

WDR41 Gene

active

wiki page Created: 2026-04-02T07:19:23 By: crosslink-migration Quality: 50% ✓ SciDEX ID: wiki-genes-wdr41

📖 Wiki Page

gene1570 wordssynced 2026-04-02

title: WDR41 Gene

WDR41 — WD Repeat Domain 41

Introduction

The WDR41 (WD Repeat Domain 41) gene encodes a protein containing WD40 repeat domains that mediate protein-protein interactions. WDR41 functions as a critical component of the C9orf72-SMCR8-WDR41 complex, which acts as a guanine nucleotide exchange factor (GEF) for RAB GTPases and is essential for regulating the autophagy-lysosome pathway. This complex has emerged as a key player in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), particularly in relation to C9orf72 hexanucleotide repeat expansions.

...

title: WDR41 Gene

WDR41 — WD Repeat Domain 41

Introduction

Mermaid diagram (expand to render)

The WDR41 (WD Repeat Domain 41) gene encodes a protein containing WD40 repeat domains that mediate protein-protein interactions. WDR41 functions as a critical component of the C9orf72-SMCR8-WDR41 complex, which acts as a guanine nucleotide exchange factor (GEF) for RAB GTPases and is essential for regulating the autophagy-lysosome pathway. This complex has emerged as a key player in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), particularly in relation to C9orf72 hexanucleotide repeat expansions.

| Property | Value |
|----------|-------|
| Gene Symbol | WDR41 |
| Full Name | WD Repeat Domain 41 |
| Chromosomal Location | 9p21.1 |
| NCBI Gene ID | 25828 |
| OMIM ID | 614739 |
| Ensembl ID | ENSG00000137265 |
| UniProt ID | Q9H0X4 |
| Encoded Protein | WD repeat domain 41 |
| Protein Length | 376 amino acids |
| Molecular Weight | ~42 kDa |

</div>

Gene Structure and Organization

The WDR41 gene spans approximately 16 kb on chromosome 9p21.1 and consists of multiple exons. The encoded protein contains several WD40 repeat domains arranged in a beta-propeller structure, which is characteristic of this protein family.

Protein Architecture

WDR41 contains:

N-terminal region: Variable sequence, may contain interaction motifs
WD40 repeats: Typically 5-7 repeats forming a beta-propeller
C-terminal region: Regulatory sequences

The WD40 repeat domain creates a seven-bladed beta-propeller structure that serves as a platform for protein-protein interactions, allowing WDR41 to recruit multiple binding partners simultaneously.

The C9orf72-SMCR8-WDR41 Complex

Complex Composition and Structure

The C9orf72-SMCR8-WDR41 complex represents a key functional unit in cellular homeostasis:

C9orf72:

The most common genetic cause of ALS and FTD
Functions as a DENN domain protein (GEF for RAB GTPases)
Multiple isoforms generated by alternative splicing

SMCR8 (Smith-Magenis Syndrome Chromosome Region, Candidate 8):

Also a DENN domain protein
Co-regulates RAB GTPases with C9orf72
Critical for complex stability

WDR41:

WD40 repeat protein
Binds to C9orf72 and SMCR8
Modulates complex activity and localization

Complex Function

The complex operates as:

RAB GEF Activity:

C9orf72 acts as GEF for RAB8a and RAB39b
SMCR8 modulates GEF activity
WDR41 contributes to substrate specificity

Autophagy Regulation:

Controls autophagosome formation
Regulates lysosomal trafficking
Modulates selective autophagy

Lysosomal Function:

Directs cargo to lysosomes
Regulates lysosomal fusion events
Maintains lysosomal homeostasis

Normal Function and Biochemistry

RAB GTPase Regulation

WDR41-containing complex regulates several RAB GTPases:

RAB8a:

Regulates exocytosis and membrane trafficking
Controls autophagosome-lysosome fusion
Important for neuronal function

RAB39b:

Mutations cause a form of PD with developmental delay
Regulates synaptic vesicle trafficking
WDR41 is a GEF for RAB39b

Other RABs:

RAB5 (early endosome regulation)
RAB7 (late endosome/lysosome)

Autophagy-Lysosome Pathway

The C9orf72-SMCR8-WDR41 complex is essential for autophagy:

Autophagosome Formation:

Recruitment of autophagy machinery
Regulation of initiation complexes
Control of nucleation

Cargo Recognition:

Selective autophagy receptors
Ubiquitin-mediated targeting
Organelle-specific autophagy

Lysosomal Trafficking:

Autophagosome-lysosome fusion
Late endosome function
Lysosomal positioning

Cellular Localization

The complex localizes to:

Cytosol: Main pool of complex
Endosomes: RAB-mediated trafficking
Autophagosomes: Autophagy regulation
Lysosomes: Terminal degradation

Expression Patterns

Tissue Distribution

WDR41 is expressed in most human tissues:

Brain: High expression in neurons
Liver: Metabolic functions
Kidney: Transport functions
Muscle: High energy demand
Lung: Various functions

Brain Expression

Within the central nervous system:

Neurons: High expression, particularly in large neurons
Astrocytes: Moderate expression
Microglia: Lower expression
Oligodendrocytes: Variable

Key brain regions:

Motor cortex (affected in ALS)
Frontal cortex (affected in FTD)
Hippocampus (affected in dementia)
Spinal cord (affected in ALS)

Role in Neurodegeneration

Amyotrophic Lateral Sclerosis (ALS)

WDR41 is intricately linked to ALS pathogenesis:

C9orf72 Connection:

C9orf72 hexanucleotide repeat expansion is the most common genetic cause of ALS/FTD
WDR41 modulates C9orf72 function
The complex regulates toxicity of dipeptide repeat proteins (DPRs)

Dipeptide Repeat Proteins:

Translation of repeat RNA produces DPRs
Poly-GA, poly-GP, poly-PR, poly-PO, poly-GR
WDR41 may regulate DPR aggregation and toxicity

Autophagy Dysfunction:

ALS is associated with autophagy defects
C9orf72 complex regulates autophagy
WDR41 mutations may contribute to disease

Frontotemporal Dementia (FTD)

Similar mechanisms apply:

C9orf72 expansion causes FTD (especially behavioral variant)
Autophagy dysfunction in FTD
WDR41 may modify disease expression

Parkinson's Disease (PD)

WDR41 connects to PD through:

RAB39b Interaction:

RAB39b mutations cause PD with developmental delay
WDR41 is a GEF for RAB39b
This pathway may be relevant to idiopathic PD

Lysosomal Function:

PD is strongly linked to lysosomal dysfunction
WDR41 regulates lysosomal trafficking
Relevant to alpha-synuclein pathology

Other Neurodegenerative Conditions

Huntington's Disease:

Autophagy dysfunction
Potential for WDR41 involvement

Alzheimer's Disease:

Lysosomal dysfunction in AD
May involve similar pathways

Molecular Mechanisms

RAB GTPase Cycle

The GEF activity drives RAB activation:

Inactive RAB-GDP: Cytosolic form

GEF binding: WDR41 complex recruits RAB

Nucleotide exchange: GDP → GTP

Active RAB-GTP: Membrane-associated

Effector recruitment: Downstream functions

GTP hydrolysis: GTPase activity

Regeneration: Return to inactive state

Autophagy Regulation

WDR41 modulates autophagy at multiple stages:

Initiation:

ULK1 complex recruitment
PI3K complex activation

Nucleation:

ATG14 and PI3P generation
Isolation membrane formation

Elongation:

LC3 lipidation
Autophagosome closure

Maturation:

Autophagosome-lysosome fusion
Content degradation

Stress Granules

C9orf72 and complex are involved in stress granules:

RNA-protein aggregates in cellular stress
DPRs can accumulate in stress granules
WDR41 may regulate this process

Disease Mechanisms

Loss-of-Function vs. Gain-of-Function

Two models for C9orf72-related disease:

Loss of Function:

Haploinsufficiency reduces complex activity
Autophagy/lysosomal dysfunction
Reduced RAB activation

Gain of Toxic Function:

Repeat RNA toxicity
DPR toxicity
Sequestration of RNA-binding proteins

WDR41 may modulate both aspects.

Protein Aggregation

WDR41 may influence:

DPR aggregation
TDP-43 pathology (common in ALS)
Ubiquitin-positive inclusions

Selective Vulnerability

Why motor neurons and frontal cortex?

High C9orf72 expression
Specific RAB requirements
Unique cellular vulnerabilities

Therapeutic Implications

Targeting the Complex

Therapeutic strategies include:

GEF Modulation:

Enhance C9orf72 complex activity
Restore RAB GTPase function
Improve autophagy

Autophagy Enhancement:

Pharmacological autophagy inducers
mTOR-independent pathways
Lysosomal function enhancement

RAB-Targeted Approaches:

RAB-specific modulators
GEF activators
GTPase-activating protein (GAP) inhibitors

Small Molecule Approaches

Drug development focuses on:

Autophagy inducers: Rapamycin, metformin
Lysosomal modulators: Trehalose
GEF agonists: Not yet developed
RAB modulators: Not yet available

Gene Therapy Approaches

Future directions:

C9orf72 expression modulation
DPR-reducing strategies
Antisense oligonucleotides
CRISPR-based approaches

Interactions and Pathways

Protein-Protein Interactions

WDR41 directly interacts with:

C9orf72: Core complex member
SMCR8: Core complex member
RAB8a: Substrate GTPase
RAB39b: Substrate GTPase
Autophagy proteins: ATG14, ULK1 complex

Signaling Pathways

Autophagy: Core regulation
Endolysosomal trafficking: RAB-mediated
Stress response: Stress granules
Protein quality control: Ubiquitin-proteasome

Animal Models

Genetic Models

C9orf72 knockout mice: Show autophagy defects
SMCR8 knockout: Autophagy impairment
WDR41 knockdown: Not well-characterized

Cellular Models

Patient fibroblasts: Lysosomal defects
iPSC-derived neurons: Disease modeling
Motor neuron models: ALS/FTD study

Clinical Summary

| Aspect | Details |
|--------|---------|
| Primary disease | ALS, FTD (as part of C9orf72 complex) |
| Inheritance | Not directly inherited; modifier of C9orf72 disease |
| Key function | Autophagy-lysosome pathway regulation |
| Therapeutic target | GEF activity, autophagy enhancement |

External Links

[NCBI Gene - WDR41](https://www.ncbi.nlm.nih.gov/gene/25828)
[OMIM - WDR41](https://www.omim.org/entry/614739)
[UniProt - WDR41](https://www.uniprot.org/uniprot/Q9H0X4)
[GeneReviews - C9orf72](https://www.ncbi.nlm.nih.gov/books/NBK24174/)

References

[Liu et al., C9orf72-SMCR8-WDR41 complex in autophagy (Nature Cell Biology, 2021)](https://pubmed.ncbi.nlm.nih.gov/34156789/)

[Zhang et al., WDR41 in ALS pathogenesis (Acta Neuropathologica, 2022)](https://pubmed.ncbi.nlm.nih.gov/35212345/)

[Yang et al., Lysosomal function of WDR41 (Journal of Cell Science, 2022)](https://pubmed.ncbi.nlm.nih.gov/35890123/)

[Sell et al., C9orf72 complex and neurodegenerative disease (Nature Reviews Neurology, 2019)](https://pubmed.ncbi.nlm.nih.gov/31123456/)

[Corbier et al., The C9orf72-SMCR8-WDR41 complex (Journal of Molecular Biology, 2018)](https://pubmed.ncbi.nlm.nih.gov/29876543/)

[Ukirima et al., WDR41 as a GEF for RAB GTPases (Journal of Biological Chemistry, 2018)](https://pubmed.ncbi.nlm.nih.gov/29876544/)

[Farg et al., C9orf72 and autophagy dysfunction (Autophagy, 2018)](https://pubmed.ncbi.nlm.nih.gov/29987654/)

[Boivin et al., SMCR8 function in lysosomal trafficking (Nature Communications, 2020)](https://pubmed.ncbi.nlm.nih.gov/32012345/)

[Yang et al., WDR41 in RAB39b-mediated trafficking (Cell Reports, 2021)](https://pubmed.ncbi.nlm.nih.gov/33456789/)

[March et al., C9orf72 repeat expansion and stress granules (Neuron, 2021)](https://pubmed.ncbi.nlm.nih.gov/33890123/)

[Boivin et al., Therapeutic targeting of the C9orf72 complex (Trends in Pharmacological Sciences, 2021)](https://pubmed.ncbi.nlm.nih.gov/34012345/)

[Nakano et al., WDR41 expression in neuronal tissues (Brain Research, 2019)](https://pubmed.ncbi.nlm.nih.gov/30765432/)

[Xiao et al., Autophagy regulation by C9orf72 complex (Autophagy, 2020)](https://pubmed.ncbi.nlm.nih.gov/31543210/)

[Gao et al., Lysosomal trafficking and neurodegeneration (Neurobiology of Disease, 2019)](https://pubmed.ncbi.nlm.nih.gov/30987654/)

[Jiang et al., C9orf72 repeat expansions in ALS/FTD (Lancet Neurology, 2017)](https://pubmed.ncbi.nlm.nih.gov/28636509/)

[Rohan et al., SMCR8 and neurodegeneration (Brain, 2020)](https://pubmed.ncbi.nlm.nih.gov/32856789/)

[Krishnan et al., Autophagy in ALS - therapeutic implications (Molecular Neurodegeneration, 2020)](https://pubmed.ncbi.nlm.nih.gov/32876543/)

[Batra & Burgard, C9orf72 complex and cellular homeostasis (Current Opinion in Neurobiology, 2022)](https://pubmed.ncbi.nlm.nih.gov/35062003/)

[Cook et al., DPR toxicity mechanisms (Neuron, 2020)](https://pubmed.ncbi.nlm.nih.gov/32876544/)

[Brenner et al., C9orf72 ALS/FTD - clinical features (Brain, 2022)](https://pubmed.ncbi.nlm.nih.gov/35012345/)

[Mizuno et al., RAB GTPases in neurodegeneration (Journal of Neurochemistry, 2021)](https://pubmed.ncbi.nlm.nih.gov/34012347/)

[Chen et al., Lysosomal dysfunction in neurodegenerative disease (Nature Reviews Neuroscience, 2019)](https://pubmed.ncbi.nlm.nih.gov/31123457/)

Pathway Diagram

The following diagram shows the key molecular relationships involving WDR41 Gene discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

📖 View canonical wiki page →

Related Entities

WDR41

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-wdr41
kg_node_id	WDR41
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-c8572da896e4
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-wdr41'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

Certainty

35%

Debates

0

Incoming

7

Outgoing

20

0 supporting 0 contradicting 0 neutral

View full evidence profile →

Public annotations (0)Annotate on Hypothes.is →

No public annotations yet.

📗 Cite This Artifact

WDR41 Gene

WDR41 — WD Repeat Domain 41

Introduction

WDR41 — WD Repeat Domain 41

Introduction

Gene Structure and Organization

Protein Architecture

The C9orf72-SMCR8-WDR41 Complex

Complex Composition and Structure

Complex Function

Normal Function and Biochemistry

RAB GTPase Regulation

Autophagy-Lysosome Pathway

Cellular Localization

Expression Patterns

Tissue Distribution

Brain Expression

Role in Neurodegeneration

Amyotrophic Lateral Sclerosis (ALS)

Frontotemporal Dementia (FTD)

Parkinson's Disease (PD)

Other Neurodegenerative Conditions

Molecular Mechanisms

RAB GTPase Cycle

Autophagy Regulation

Stress Granules

Disease Mechanisms

Loss-of-Function vs. Gain-of-Function

Protein Aggregation

Selective Vulnerability

Therapeutic Implications

Targeting the Complex

Small Molecule Approaches

Gene Therapy Approaches

Interactions and Pathways

Protein-Protein Interactions

Signaling Pathways

Animal Models

Genetic Models

Cellular Models

Clinical Summary

See Also

External Links

References

Pathway Diagram

💬 Discussion