DNM3 — Dynamin 3

DNM3 — Dynamin 3

Overview

DNM3 (Dynamin 3) encodes a brain-specific GTPase that plays critical roles in synaptic vesicle endocytosis, dendritic spine morphogenesis, and postsynaptic receptor trafficking. As one of three dynamin isoforms in mammals, DNM3 exhibits unique expression patterns and functions that distinguish it from the more ubiquitously expressed dynamin 1 and dynamin 2[@praefcke2004].

Located on chromosome 1p31.1, DNM3 produces a 864-amino acid protein with a molecular weight of approximately 96 kDa. The protein is highly enriched in the brain, particularly in the hippocampus and cerebral cortex, where it localizes to dendritic spines and postsynaptic densities[@ferguson2007]. This specialized expression pattern reflects DNM3's critical functions in excitatory synaptic transmission and plasticity.

Gene Information

<div class="infobox infobox-gene">

| Property | Value |
|-----------|-------|
| Gene Symbol | DNM3 |
| Full Name | Dynamin 3 |
| Chromosome | 1p31.1 |
| NCBI Gene ID | [27037](https://www.ncbi.nlm.nih.gov/gene/27037) |
| Ensembl ID | [ENSG00000197933](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000197933) |
| UniProt ID | [Q9UQ16](https://www.uniprot.org/uniprot/Q9UQ16) |
| OMIM | 611347 |
| Protein Type | GTPase (mechanochemical enzyme) |
| Expression | Brain-specific |
| Molecular Weight | ~96 kDa |
| Associated Diseases | Alzheimer's disease, Parkinson's disease, intellectual disability, schizophrenia |

</div>

Normal Function

DNM3 Structure and Mechanism

DNM3 — Dynamin 3

Overview

DNM3 (Dynamin 3) encodes a brain-specific GTPase that plays critical roles in synaptic vesicle endocytosis, dendritic spine morphogenesis, and postsynaptic receptor trafficking. As one of three dynamin isoforms in mammals, DNM3 exhibits unique expression patterns and functions that distinguish it from the more ubiquitously expressed dynamin 1 and dynamin 2[@praefcke2004].

Located on chromosome 1p31.1, DNM3 produces a 864-amino acid protein with a molecular weight of approximately 96 kDa. The protein is highly enriched in the brain, particularly in the hippocampus and cerebral cortex, where it localizes to dendritic spines and postsynaptic densities[@ferguson2007]. This specialized expression pattern reflects DNM3's critical functions in excitatory synaptic transmission and plasticity.

Gene Information

<div class="infobox infobox-gene">

| Property | Value |
|-----------|-------|
| Gene Symbol | DNM3 |
| Full Name | Dynamin 3 |
| Chromosome | 1p31.1 |
| NCBI Gene ID | [27037](https://www.ncbi.nlm.nih.gov/gene/27037) |
| Ensembl ID | [ENSG00000197933](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000197933) |
| UniProt ID | [Q9UQ16](https://www.uniprot.org/uniprot/Q9UQ16) |
| OMIM | 611347 |
| Protein Type | GTPase (mechanochemical enzyme) |
| Expression | Brain-specific |
| Molecular Weight | ~96 kDa |
| Associated Diseases | Alzheimer's disease, Parkinson's disease, intellectual disability, schizophrenia |

</div>

Normal Function

DNM3 Structure and Mechanism

Dynamin 3 is a member of the dynamin family of large GTPases characterized by[@praefcke2004]:

• GTPase domain: Catalyzes GTP hydrolysis, providing mechanical energy for membrane fission
• Pleckstrin homology (PH) domain: Binds phosphatidylinosolipids, localizing dynamin to membrane sites
• GTPase effector domain (GED): Regulates assembly and GTPase activity
• Proline-rich domain (PRD): Mediates interactions with SH3 domain-containing proteins

Key Biological Functions

DNM3 participates in several critical neuronal processes[@lu2007]:

• Postsynaptic receptor endocytosis: DNM3 regulates AMPA receptor internalization during synaptic plasticity, a key mechanism underlying learning and memory. This function is distinct from dynamin 1's presynaptic role in synaptic vesicle recycling.
• Dendrite morphogenesis: DNM3 is involved in dendrite arborization and spine formation through regulation of membrane trafficking and cytoskeletal dynamics[@yang2023].
• Synaptic plasticity: By controlling postsynaptic receptor trafficking, DNM3 modulates long-term potentiation (LTP) and long-term depression (LTD), the cellular correlates of learning and memory.
• Membrane remodeling: DNM3 catalyzes membrane fission events essential for vesicle formation and trafficking in neuronal processes.

Expression Pattern

DNM3 shows brain-specific expression with highest levels in[@ramachandran2009]:

• Hippocampus: CA1-CA3 regions and dentate gyrus
• Cerebral cortex: Layers II-VI, particularly pyramidal neurons
• Cerebellum: Purkinje cells
• Subcellular localization: Dendritic spines, postsynaptic densities, and dendritic shafts

Role in Neurodegeneration

Alzheimer's Disease

DNM3 is implicated in AD pathogenesis through multiple mechanisms[@gong2019]:

Synaptic dysfunction: DNM3 expression is reduced in AD brain, contributing to synaptic vesicle trafficking deficits and impaired neurotransmitter release.

Tau pathology interaction: DNM3 interacts with tau protein, and tau phosphorylation affects DNM3 function[@iwata2020]. Pathological tau accumulations disrupt DNM3 localization and activity.

Beta-amyloid effects: Aβ exposure reduces DNM3 expression in neurons, and this reduction correlates with cognitive decline in mouse models.

Postsynaptic deficits: AD is characterized by early synaptic loss. DNM3 regulates AMPA receptor trafficking essential for synaptic function, and its dysfunction may contribute to postsynaptic deficits observed in AD.

Therapeutic implications: Restoring DNM3 function may help recover synaptic plasticity in AD.

Parkinson's Disease

DNM3 contributes to PD through several mechanisms[@liu2022]:

Alpha-synuclein interaction: DNM3 interacts with alpha-synuclein, and this interaction is disrupted in PD[@suzuki2022]. Alpha-synuclein aggregation may sequester DNM3 and impair its function.

Vesicle trafficking: DNM3 supports endosomal and synaptic vesicle trafficking that is compromised in PD.

Dopaminergic neuron vulnerability: DNM3 expression in substantia nigra pars compacta neurons may contribute to their selective vulnerability.

Intellectual Disability

DNM3 variants are associated with neurodevelopmental disorders[@takahashi2021]:

• De novo missense variants cause intellectual disability without consistent dysmorphic features
• Variants affect GTPase activity or protein-protein interactions
• Mouse models show learning and memory deficits
• May involve impaired dendritic spine development

Schizophrenia

DNM3 dysregulation contributes to schizophrenia:

• Reduced DNM3 expression in prefrontal cortex
• Associated with synaptic dysfunction and cognitive deficits
• Genetic variants may increase disease risk
• May affect NMDA receptor trafficking

Molecular Mechanisms

GTP Hydrolysis Cycle

DNM3 catalyzes a conformational cycle critical for membrane fission:

Protein Interactions

DNM3 interacts with numerous synaptic proteins:

| Interactor | Interaction Type | Function |
|------------|------------------|----------|
| Amphiphysin | Direct binding | Scaffolding and recruitment |
| Dynamitin | Indirect via dynein | Transport regulation |
| PSD-95 | Direct binding | Postsynaptic targeting |
| GRIP1 | Direct binding | AMPA receptor interaction |
| Synaptojanin | Coordinated function | Endocytic accessory |
| Endophilins | Coordinated function | Membrane curvature |

Animal Models and Research Findings

Knockout Mouse Phenotypes

DNM3-deficient mice exhibit[@tanaka2020]:

• Viable and fertile with subtle neurological phenotypes
• Impaired spatial learning and memory
• Altered dendritic spine morphology
• Reduced long-term potentiation
• Enhanced long-term depression
• Normal basic motor function

Transgenic and Overexpression Studies

• DNM3 overexpression enhances spine density
• Rescue of knockout phenotypes possible
• Viral vector delivery improves function

Human Studies

• DNM3 expression reduced in AD and PD brain
• Genetic variants associated with disease risk
• CSF biomarker potential under investigation

Therapeutic Strategies

Gene Therapy Approaches

Recent advances offer promising strategies[@mori2024]:

• AAV-mediated DNM3 delivery to neurons
• CRISPR-based correction of pathogenic variants
• shRNA knockdown for dominant-negative forms

Small Molecule Modulators

Pharmacological approaches include:

• Dynamin GTPase activity enhancers
• Protein-protein interaction disruptors
• Phosphorylation state modulators

Biomarker Development

DNM3 as a biomarker[@petrov2024]:

• CSF DNM3 levels correlate with disease stage
• Potential for treatment response monitoring
• Need for assay standardization

Interactions and Signaling Network

DNM3 participates in multiple signaling pathways:

| Pathway | Interaction | Function |
|---------|-------------|----------|
| Clathrin-mediated endocytosis | Core component | Vesicle formation |
| AMPA receptor trafficking | Direct binding | Synaptic plasticity |
| PSD-95 complex | Scaffold interaction | Postsynaptic organization |
| Mitochondrial dynamics | Indirect via transport | Energy homeostasis |

See Also

• [Dynamin 1](/genes/dnm1)
• [Dynamin 2](/genes/dnm2)
• [Synaptic Vesicle Cycling](/mechanisms/synaptic-vesicle-cycling)
• [Dendritic Spines](/mechanisms/dendritic-spines)
• [AMPA Receptor Trafficking](/mechanisms/ampa-receptor-trafficking)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Synaptic Plasticity](/mechanisms/synaptic-plasticity)

References