MYO6 encodes Myosin VI, an unconventional myosin motor protein with unique reverse directionality—moving towards the minus (pointed) end of actin filaments, opposite to all other characterized myosins[1]. This distinctive motor property enables Myosin VI to perform specialized cellular functions in intracellular transport, endocytosis, organelle positioning, and synaptic function[2]. MYO6 has emerged as a gene of interest in neurodegenerative diseases, particularly Parkinson's disease, where it plays important roles in synaptic vesicle trafficking and axonal transport[3].
| MYO6 — Myosin VI | |
|---|---|
| Gene Symbol | MYO6 |
| Full Name | Myosin VI |
| Chromosome | 6q13 |
| NCBI Gene ID | [4656](https://www.ncbi.nlm.nih.gov/gene/4656) |
| OMIM | 600970 |
| Ensembl ID | ENSG00000128595 |
| UniProt ID | [Q9UMR5](https://www.uniprot.org/uniprot/Q9UMR5) |
| Associated Diseases | Deafness, Parkinson's Disease, Alzheimer's Disease |
| Property | Value |
|---|---|
| Molecular Weight | ~170 kDa (heavy chain) |
| Motor Class | Unconventional myosin (class VI) |
| Directionality | Minus-end directed (unique among myosins) |
| Motor Domain | N-terminal motor domain with ATPase activity |
| Tail Domain | C-terminal cargo-binding domain (dimerization) |
| Tissue Expression | Inner ear, kidney, brain, testis |
Myosin VI has several distinctive structural features that enable its unique function[2:1][4]:
Reverse Directionality: The motor domain moves towards the minus end of actin filaments, contrary to most other myosins which move towards the plus end. This is conferred by structural features in the motor domain and lever arm.
Dimerization Domain: The tail region contains a coiled-coil domain that mediates dimerization, enabling processive movement along actin filaments.
Cargo-Binding Domain: The C-terminal region binds to various cargo adaptors, including optineurin, GIPC, and other scaffolding proteins.
Lever Arm: Myosin VI has an extended lever arm that contributes to its step size and force generation.
Myosin VI performs multiple essential cellular functions[1:1][2:2][4:1]:
Myosin VI is a key motor for endocytosis:
Myosin VI functions as a processive motor:
Myosin VI contributes to autophagy through[5]:
Myosin VI plays roles in:
In neurons, Myosin VI has critical roles in[6][7][8]:
Synaptic Vesicle Trafficking: Myosin VI localizes to synaptic vesicles and participates in their transport within presynaptic terminals[3:1].
AMPA Receptor Trafficking: Myosin VI regulates the trafficking of AMPA-type glutamate receptors in postsynaptic dendritic spines, influencing synaptic plasticity[7:1].
Dendritic Spine Morphology: Myosin VI is enriched in postsynaptic structures and regulates spine shape and size[8:1].
Neurotransmitter Release: Myosin VI contributes to synaptic vesicle exocytosis and endocytosis cycles.
Myosin VI participates in axonal transport mechanisms[9]:
Myosin VI may influence mitochondrial dynamics:
| Tissue | Expression Level | Key Functions |
|---|---|---|
| Inner ear (hair cells) | Highest | Stereocilia organization, mechanotransduction |
| Kidney | High | Endocytosis, membrane trafficking |
| Brain | Moderate | Synaptic function, transport |
| Testis | Moderate | Spermatogenesis |
| Heart | Low | Various |
| Liver | Low | Endocytosis |
In the brain, Myosin VI shows region-specific expression:
This pattern overlaps with brain regions affected in Parkinson's and Alzheimer's diseases, suggesting potential relevance to neurodegeneration.
MYO6 mutations cause autosomal recessive nonsyndromic hearing loss[10]:
| Feature | Details |
|---|---|
| Inheritance | Autosomal recessive |
| Phenotype | Prelingual or postlingual sensorineural deafness |
| Mechanism | Impaired hair cell function in inner ear |
| Pathology | Degeneration of stereocilia and hair cells |
Myosin VI is implicated in Parkinson's disease through multiple mechanisms[3:2][11]:
Synaptic Vesicle Dysfunction: Myosin VI deficiency impairs synaptic vesicle trafficking, potentially contributing to dopaminergic neuron vulnerability[3:3].
Axonal Transport Defects: Impaired transport of vesicular cargo may affect neuronal connectivity and survival.
Autophagy Dysfunction: Myosin VI's role in autophagy links to protein aggregate clearance—defects may contribute to alpha-synuclein accumulation.
Mitochondrial Function: Altered mitochondrial trafficking and quality control.
Myosin VI may contribute to AD pathogenesis through:
Myosin VI deficiency leads to[6:1][7:2]:
Defective Myosin VI function causes[9:1]:
Myosin VI deficiency impairs[5:1]:
Altered Myosin VI affects:
Myosin VI dysfunction disrupts[1:3]:
Myosin VI interacts with numerous proteins that are relevant to neurodegenerative processes[12][13]:
| Interactor | Function | Relevance to Neurodegeneration |
|---|---|---|
| Optineurin | Autophagy receptor | Links to mitophagy and PD |
| GIPC | Scaffold protein | Synaptic signaling |
| Dab2 | Endocytosis adaptor | Cargo sorting |
| Synectin | Axon guidance | Axonal pathfinding |
| LMTK1 | Kinase | Neuronal function |
| Rab GTPases | Vesicle trafficking | Synaptic vesicle cycle |
Myosin VI participates in multiple signaling cascades:
Parkin-Dependent Mitophagy: Myosin VI interacts with optineurin to facilitate parkin-mediated mitophagy. Dysfunction leads to impaired mitochondrial quality control—a key mechanism in PD pathogenesis[13:1].
mTOR Signaling: Myosin VI localization to lysosomes influences mTORC1 signaling, affecting cellular metabolism and autophagy.
AMPA Receptor Signaling: Through interaction with GRIP1 and PICK1, Myosin VI modulates AMPA receptor trafficking relevant to synaptic plasticity in AD[7:3].
TGF-β Signaling: Myosin VI participates in TGF-β receptor trafficking, with implications for neuroinflammation.
Myosin VI function is regulated by multiple PTMs:
Phosphorylation: Casein kinase II and other kinases phosphorylate Myosin VI, regulating its motor activity and cargo binding[14].
Ubiquitination: Myosin VI is ubiquitinated by parkin and other E3 ligases, targeting it for degradation or autophagy.
Myristoylation: Palmitoylation regulates Myosin VI membrane association and localization.
Multiple studies have investigated Myosin VI in PD[3:4][11:1][13:2]:
Myosin VI alterations in AD include[15][16][^20]:
Targeting Myosin VI function offers potential therapeutic strategies:
Small Molecule Modulators: Compounds enhancing Myosin VI motor function could improve synaptic vesicle trafficking.
Gene Therapy: Viral vector delivery of wild-type MYO6 may restore function.
Protein-Protein Interaction Inhibitors: Blocking harmful interactions while preserving beneficial ones.
| Model | Phenotype | Relevance |
|---|---|---|
| Myo6 knock-out | Deafness, vestibular dysfunction | Hearing loss mechanism |
| Myo6 knock-in (snell) | Deafness, circling behavior | Inner ear development |
| Myo6 conditional KO | Synaptic defects | Neuronal function |
| Myo6/SNCA double mutant | Enhanced pathology | PD model |
Myosin VI is a challenging drug target:
| Approach | Status | Challenges |
|---|---|---|
| Small molecule agonists | Preclinical | Motor complex structure |
| Antisense oligonucleotides | Research | Delivery to CNS |
| Gene therapy | Research | Viral delivery |
| Protein replacement | Research | Protein stability |
Myosin VI levels may serve as:
Myosin VI is a unique motor protein with essential roles in neurodegeneration:
Unique Directionality: The only known minus-end directed myosin, enabling specialized cellular functions.
Synaptic Function: Critical for synaptic vesicle trafficking, AMPA receptor trafficking, and dendritic spine morphology.
Autophagy Role: Partners with optineurin in selective autophagy, particularly mitophagy—central to PD pathogenesis.
Disease Links: Altered in both Parkinson's and Alzheimer's disease, with genetic associations in some populations.
Therapeutic Potential: Modulating Myosin VI function could restore synaptic trafficking and autophagy deficits.
Myosin VI structure and function. 2013. ↩︎ ↩︎ ↩︎ ↩︎
MYO6 and hereditary deafness. 2013. ↩︎ ↩︎ ↩︎
Myosin VI and synaptic function. 2020. ↩︎ ↩︎ ↩︎
Myosin VI in AMPA receptor trafficking. 2016. ↩︎ ↩︎ ↩︎ ↩︎ ↩︎
Myosin VI and Parkinson's disease genetic susceptibility. 2020. ↩︎ ↩︎ ↩︎
Myosin VI in axonal transport. 2021. ↩︎ ↩︎
Myosin VI in autophagy. 2018. ↩︎ ↩︎ ↩︎
Myosin VI in postsynaptic density and memory formation. 2020. ↩︎ ↩︎ ↩︎
Myosin VI and stereocilia development in the inner ear. 2018. ↩︎
Myosin VI regulation by phosphorylation in neurons. 2020. ↩︎