CCNF Protein (Cyclin F)

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CCNF Protein (Cyclin F)

title: CCNF Protein
<div class="infobox infobox-protein">
<table>
<tr><th>Protein Name</th><td>Cyclin F</td></tr>
<tr><th>Gene</th><td>[CCNF](/genes/ccnf)</td></tr>
<tr><th>UniProt ID</th><td>[Q96VD8](https://www.uniprot.org/uniprot/Q96VD8)</td></tr>
<tr><th>PDB Structure</th><td>6QXM, 5K8W, 5HRS</td></tr>
<tr><th>Molecular Weight</th><td>786 aa (~89.5 kDa)</td></tr>
<tr><th>Subcellular Localization</th><td>Nucleus, Cytoplasm</td></tr>
<tr><th>Protein Family</th><td>F-box protein family, Cyclin family</td></tr>
<tr><th>Aliases</th><td>FBXO1, CycF</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

CCNF Protein (Cyclin F)

Overview

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CCNF Protein (Cyclin F)

Overview

Mermaid diagram (expand to render)

Ccnf Protein (Cyclin F) plays an important role in the study of neurodegenerative diseases. This page provides comprehensive information about this topic, including its mechanisms, significance in disease processes, and therapeutic implications.

Introduction

Cyclin F (encoded by the CCNF gene) is a unique member of the cyclin family that functions as the substrate recognition component of the SCF (Skp1-Cul1-F-box) ubiquitin ligase complex[@cardozo2005]. Unlike conventional cyclins, Cyclin F does not regulate cyclin-dependent kinases (CDKs) but instead plays a critical role in ubiquitin-mediated protein degradation. Pathogenic variants in CCNF have been firmly linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), making it a protein of significant interest in neurodegenerative disease research[@williams2016].

Structure

Domain Architecture

Cyclin F possesses a distinctive domain organization that enables its functions as an E3 ubiquitin ligase:

F-box Domain (residues 43-93): This conserved domain mediates binding to the Skp1 adaptor protein, incorporating CCNF into the SCF ubiquitin ligase complex[@skaar2009]. The F-box serves as the critical link between the substrate recognition module and the Cul1 scaffold.
Leucine-Rich Repeats (LRRs) (residues 124-280): The LRR domain provides the structural basis for substrate recognition. These repeats form a curved solenoid structure that recognizes specific degron motifs in target proteins[@tschpe2020].
N-terminal Domain: Contains regulatory elements including phosphorylation sites that modulate protein-protein interactions and substrate binding affinity.
C-terminal Regions: House additional protein interaction motifs and post-translational modification sites.

Post-Translational Modifications

Cyclin F activity is regulated by several post-translational modifications:

Phosphorylation: Multiple serine/threonine phosphorylation sites regulate substrate binding and SCF complex assembly. Casein kinase 2 (CK2) phosphorylation enhances CCNF activity[@shimizu2018].
Ubiquitination: As an E3 ligase, CCNF itself can be ubiquitinated, leading to proteasomal degradation in a feedback regulatory mechanism.
Sumoylation: SUMO modification influences nuclear-cytoplasmic trafficking and protein stability.

Normal Function

SCF^CCNF Ubiquitin Ligase Activity

Cyclin F functions as the substrate recognition component of the SCF^CCNF ubiquitin ligase complex, which catalyzes the attachment of ubiquitin chains to target proteins, marking them for proteasomal degradation[@petroski2005]. This process is essential for:

Protein Quality Control: Elimination of misfolded, damaged, or oxidized proteins

Cell Cycle Regulation: Timing of G1/S transition and S-phase progression

Signal Transduction: Turnover of signaling intermediates

Transcriptional Regulation: Control of transcription factor stability

Key Substrate Classes

SCF^CCNF targets diverse substrate classes:

RNA-Binding Proteins: Including [TDP-43](/mechanisms/tdp-43-proteinopathy) (TARDBP), FUS, and hnRNPs
Cell Cycle Regulators: Cyclin-dependent kinase inhibitors
Transcription Factors: Nuclear receptors and co-activators
DNA Repair Proteins: Components of the DNA damage response

Tissue Expression

CCNF is expressed in most tissues, with highest expression in:

[Neurons](/entities/neurons) (particularly cortical and motor neurons)
Testis
Lymphocytes

Role in Neurodegeneration

Amyotrophic Lateral Sclerosis (ALS)

CCNF mutations were first identified as causative in familial ALS in 2016, with subsequent studies confirming its role in both familial and sporadic forms[@lee2018]. The disease mechanisms include:

Loss of Ubiquitination Function: Mutations in the LRR domain impair substrate recognition, reducing the degradation of neurotoxic proteins. This leads to:

Accumulation of ubiquitinated protein aggregates
Impaired clearance of TDP-43 aggregates (a hallmark of ALS/FTD)
Dysregulation of RNA metabolism

Gain of Toxic Function: Some mutations may confer novel toxic properties:

Formation of cytoplasmic aggregates that sequester normal proteins
Interference with other F-box proteins
Disruption of nuclear import/export

Exacerbating Factors:

Oxidative stress
Mitochondrial dysfunction
[Excitotoxicity](/mechanisms/excitotoxicity)

Frontotemporal Dementia (FTD)

CCNF is classified as a causal gene for FTD, particularly the FTD-ALS spectrum[@gagliardi2018]:

CCNF mutations account for 2-5% of familial FTD cases
Neuropathology shows TDP-43 positive inclusions
Clinical presentation includes behavioral variant FTD and progressive aphasia

Protein Aggregation Pathways

The role of CCNF in protein aggregation involves:

TDP-43 Pathology: SCF^CCNF normally ubiquitinates TDP-43. Loss of function leads to TDP-43 accumulation[@fecto2021].

Aggregate Sequestration: Mutant CCNF can be incorporated into stress granules and aggregates, further disrupting cellular proteostasis.

Interplay with Other ALS/FTD Genes: CCNF interacts genetically and functionally with:

[C9orf72](/entities/c9orf72) (hexanucleotide repeat expansion)
TARDBP (TDP-43)
FUS
OPTN
TBK1

Mechanistic Summary

CCNF Mutation → Impaired substrate recognition → Reduced ubiquitination
↓
Accumulation of neurotoxic proteins (TDP-43, etc.)
↓
Protein aggregate formation
↓
Neuronal dysfunction and death

Therapeutic Strategies

Proteostasis Enhancement

Given the central role of impaired protein degradation in CCNF-related disease:

Proteasome Enhancers: Compounds that boost proteasome activity (e.g., natural products like polyphenols)
[Autophagy](/entities/autophagy) Inducers: Enhance aggregate clearance via autophagy
Molecular Chaperones: Improve protein folding capacity

Gene Therapy Approaches

Antisense Oligonucleotides (ASOs): Target mutant CCNF transcripts for degradation
CRISPR-Cas9: Correct pathogenic mutations or modulate expression
RNAi: Knockdown of mutant allele expression

Small Molecule Interventions

Kinase Inhibitors: Modulate post-translational modifications
Aggregate-Break ing Compounds: Disassemble existing aggregates
Neuroprotective Agents: Target downstream pathways

Research Pipeline

| Approach | Stage | Challenges |
|----------|-------|------------|
| ASOs | Preclinical | Delivery to CNS |
| Proteasome enhancers | Early clinical | Specificity |
| Gene therapy | Preclinical | Safety |

Key Research Findings

Discovery of CCNF Mutations in ALS/FTD

The seminal study by Williams et al. (2016) identified CCNF as an ALS/FTD causative gene through exome sequencing of familial cases[@williams2016]. This finding was subsequently validated in multiple cohorts worldwide.

SCF^CCNF and TDP-43

Laboratory studies have demonstrated that SCF^CCNF directly ubiquitinates TDP-43, providing a mechanistic link between CCNF dysfunction and the hallmark protein aggregates of ALS/FTD[@fecto2021].

Animal Models

Transgenic mouse models expressing mutant CCNF show:

Progressive motor neuron degeneration
TDP-43 pathology
Reduced lifespan
Behavioral deficits

CCNF interacts with several key cellular pathways:

[Ubiquitin-Proteasome System](/mechanisms/ubiquitin-proteasome-system): Core degradation pathway
[Protein Aggregation](/mechanisms/protein-aggregation): Aggregate formation in disease
[RNA Metabolism](/mechanisms/rna-metabolism): TDP-43/FUS-related pathways
[DNA Damage Response](/mechanisms/dna-damage-response): Genome stability maintenance
[Autophagy](/mechanisms/autophagy): Aggregate clearance pathway

[CCNF Gene](/genes/ccnf): Gene-level information
[Amyotrophic Lateral Sclerosis (ALS)](/diseases/amyotrophic-lateral-sclerosis): Disease context
[Frontotemporal Dementia (FTD)](/diseases/frontotemporal-lobar-degeneration): Disease context
[F-box Proteins](/proteins/fbxo-proteins): Protein family context
[SCF Complex](/mechanisms/scf-ubiquitin-ligase): Complex architecture
[TDP-43 Pathology](/mechanisms/tdp-43-pathology): Key disease mechanism

Overview

Background

The study of Ccnf Protein (Cyclin F) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

Corticobasal Syndrome (CBS)

While CCNF mutations are well-established causes of [Amyotrophic Lateral Sclerosis (ALS)](/diseases/amyotrophic-lateral-sclerosis) and [Frontotemporal Dementia (FTD)](/diseases/frontotemporal-lobar-degeneration), emerging evidence suggests CCNF may also play a role in [Corticobasal Syndrome (CBS)](/diseases/corticobasal-syndrome)[@expanding2025].

Novel p.M394L Variant in CBS

A 2025 case report described a novel heterozygous missense variant (p.Met394Leu) in the CCNF gene in a patient of South Asian origin presenting with CBS[@expanding2025]:

Case Presentation:

48-year-old patient with progressive cognitive decline
Behavioral disturbances and asymmetric motor symptoms
Brain imaging showed asymmetric atrophy and hypometabolism in left temporoparietal and prefrontal regions
Family history indicated autosomal dominant inheritance pattern of progressive cognitive decline

Genetic Analysis:

Whole-exome sequencing identified CCNF p.M394L variant
Located in the Leucine-Rich Repeat (LRR) domain (residues 124-280)
Structural modeling suggested deleterious effects
In-silico prediction tools predicted pathogenic impact

Significance:
This finding expands the genetic spectrum of CBS and suggests that CCNF variants may contribute to the pathogenesis of CBS in some patients[@expanding2025]. The variant's location in the LRR domain, which is critical for substrate recognition, is consistent with a loss-of-function mechanism similar to that proposed for CCNF-related ALS/FTD.

Implications for CBS Genetics

The identification of CCNF variants in CBS adds to the growing understanding of genetic contributions to CBS:

| Gene | Associated Pathology | CBS Relevance |
|------|---------------------|---------------|
| [MAPT](/proteins/tau) | 4R Tau | Primary cause of CBD |
| PSP | Tau (4R) | Common CBS mimic |
| C9orf72 | TDP-43 | CBS in some cases |
| GRN | TDP-43 | CBS in some cases |
| CCNF | TDP-43 | Novel CBS association |

See also: [Genetic Risk Factors for CBS](/diseases/corticobasal-syndrome#genetics)

References

[@cardozo2005]: [Cardozo et al., SCF ubiquitin ligases in cell cycle control (2005)](https://doi.org/10.1016/j.tcb.2005.09.003)
[@williams2016]: [Williams et al., CCNF mutations cause familial ALS and FTD (2016)](https://doi.org/10.1016/j.neuron.2016.05.017)
[@skaar2009]: [Skaar et al., F-box proteins in the ubiquitin-proteasome system (2009)](https://doi.org/10.1038/nrm2831)
[@tschpe2020]: [Tschöpe et al., Structure of the CCNF LRR domain (2020)](https://doi.org/10.1074/jbc.RA120.014456)
[@shimizu2018]: [Shimizu et al., CK2 phosphorylation of CCNF (2018)](https://doi.org/10.1016/j.bbamcr.2018.03.012)
[@petroski2005]: [Petroski & Deshaies, Function and regulation of cullin-RING ubiquitin ligases (2005)](https://doi.org/10.1016/j.tibs.2005.09.005)
[@lee2018]: [Lee et al., CCNF in neurodegenerative disease (2018)](https://doi.org/10.1007/s12035-018-1120-2)
[@gagliardi2018]: [Gagliardi et al., CCNF mutations in FTD-ALS spectrum (2018)](https://doi.org/10.1007/s00401-018-1873-4)
[@fecto2021]: [Fecto et al., TDP-43 ubiquitination by SCF^CCNF (2021)](https://doi.org/10.1093/brain/awab120)
[@ai2020]: [Ai et al., CCNF dysfunction in ALS models (2020)](https://doi.org/10.1016/j.neurobiolaging.2020.01.012)

Pathway Diagram

The following diagram shows the key molecular relationships involving CCNF Protein (Cyclin F) discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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CCNF Protein (Cyclin F)

CCNF Protein (Cyclin F)

CCNF Protein (Cyclin F)

Overview

CCNF Protein (Cyclin F)

CCNF Protein (Cyclin F)

Overview

Introduction

Structure

Domain Architecture

Post-Translational Modifications

Normal Function

SCF^CCNF Ubiquitin Ligase Activity

Key Substrate Classes

Tissue Expression

Role in Neurodegeneration

Amyotrophic Lateral Sclerosis (ALS)

Frontotemporal Dementia (FTD)

Protein Aggregation Pathways

Mechanistic Summary

Therapeutic Strategies

Proteostasis Enhancement

Gene Therapy Approaches

Small Molecule Interventions

Research Pipeline

Key Research Findings

Discovery of CCNF Mutations in ALS/FTD

SCF^CCNF and TDP-43

Animal Models

Related Pathways

Related Pages

Overview

Background

Corticobasal Syndrome (CBS)

Novel p.M394L Variant in CBS

Implications for CBS Genetics

References

See Also

Pathway Diagram