| SLC39A14 | |
|---|---|
| Gene Symbol | SLC39A14 |
| Full Name | Solute Carrier Family 39 Member 14 |
| Also Known As | ZIP14, Zrt- and Irt-like Protein 14 |
| Chromosomal Location | 8p22 |
| NCBI Gene ID | [91252](https://www.ncbi.nlm.nih.gov/gene/91252) |
| OMIM | [608767](https://www.omim.org/entry/608767) |
| Ensembl ID | ENSG00000146373 |
| UniProt ID | [Q5HYNY4](https://www.uniprot.org/uniprot/Q5HYNY4) |
| Protein Class | Solute carrier, ZIP transporter family |
| Associated Diseases | Parkinson's Disease, Manganese Metabolism Disorder, Childhood Parkinsonism-Dystonia |
SLC39A14 (Solute Carrier Family 39 Member 14), also known as ZIP14, is a membrane transporter that facilitates the uptake of zinc and manganese into cells. The SLC39 family, also called the ZIP (Zrt-, Irt-like Protein) family, comprises 14 members in humans that regulate zinc and manganese homeostasis. These metal ions are essential cofactors for hundreds of enzymes and are critical for cellular function, but excess accumulation can be highly toxic. SLC39A14 is uniquely positioned as a high-affinity manganese transporter that also transports zinc, and its dysfunction leads to a distinctive clinical syndrome characterized by manganese accumulation in the brain, resulting in parkinsonism, dystonia, and cognitive impairment[1][2].
The connection between SLC39A14 and neurodegeneration extends beyond the directly associated manganese metabolism disorder. Manganese is an essential trace element required for the function of several enzymes, including arginase, glutamine synthetase, and manganese superoxide dismutase (MnSOD). However, excess manganese accumulates in the basal ganglia, particularly the globus pallidus, causing a condition known as manganism that shares features with Parkinson's disease. Understanding SLC39A14's role in metal homeostasis provides insight into how metal dysregulation contributes to neurodegenerative processes in AD, PD, and related conditions[3][4].
SLC39A14 encodes ZIP14, a membrane transporter that mediates cellular uptake of zinc and manganese. As a member of the SLC39 (ZIP) family, it plays a critical role in maintaining metal homeostasis throughout the body. Loss-of-function mutations in SLC39A14 cause a hereditary manganese metabolism disorder characterized by childhood-onset parkinsonism-dystonia, hypermanganesemia, and hepatic dysfunction. The condition results from impaired manganese efflux, leading to accumulation in the basal ganglia and subsequent neurotoxicity. Beyond this monogenic disorder, SLC39A14 dysregulation has been implicated in idiopathic Parkinson's disease, where altered manganese handling may contribute to pathogenesis. The transporter also affects zinc homeostasis, linking it to broader neurodegenerative processes involving metal ion dysregulation. Therapeutic strategies targeting SLC39A14 or metal homeostasis more broadly are under investigation for neurodegeneration[5][6].
SLC39A14/ZIP14 is a multi-pass transmembrane transporter:
The transporter functions as a dimer or higher-order oligomer, with each subunit capable of metal transport.
ZIP14 operates as a proton-coupled metal symporter:
Transport characteristics:
ZIP14 transports multiple divalent metals:
| Metal | Affinity | Physiological Role |
|---|---|---|
| Manganese (Mn2+) | High | Enzyme cofactor, neurotransmitter synthesis |
| Zinc (Zn2+) | Moderate | Enzyme cofactor, signaling |
| Iron (Fe2+) | Lower | Iron homeostasis |
| Cadmium (Cd2+) | Low | Toxic metal |
SLC39A14 expression is regulated by:
SLC39A14 is central to cellular metal balance:
Zinc Homeostasis
Manganese Homeostasis
Iron Metabolism
SLC39A14 is expressed in:
In the nervous system:
Neuronal Metal Handling
Synaptic Function
Glial Function
Biallelic loss-of-function mutations in SLC39A14 cause a distinct disorder:
Clinical Features
Genetics
Pathogenesis
Diagnosis
Treatment
SLC39A14 connections to PD:
Manganese Handling
Zinc Dysregulation
Neuroinflammation
Therapeutic Implications
In AD:
Zinc Dysregulation
Metal Homeostasis
Synaptic Function
SLC39A14 expression:
In brain:
Chelation Therapy
Metal Modulation
Neuroprotective Strategies
| Partner | Relationship | Function |
|---|---|---|
| SLC39A8 (ZIP8) | Homolog | Related metal transporter |
| ZnT family | Partner | Zinc efflux |
| DMT1 | Partner | Metal transport |
| Fpn (ferroportin) | Partner | Iron export |
| Metallothioneins | Partner | Metal binding |
Hentze MW, et al. Zinc and manganese transporters: from physiology to disease. Cell. 2004. ↩︎
Fujishiro H, et al. Zinc transporters in neurodegeneration. Brain Research Bulletin. 2012. ↩︎
Gao J, et al. Manganese-induced neurotoxicity: from synapses to behavior. Neurochemical Research. 2019. ↩︎
Chen P, et al. Manganese homeostasis and neurotoxicity. Progress in Neurobiology. 2019. ↩︎
Taylor CA, et al. SLC39A14 mutations and manganese metabolism disorders. Lancet Neurology. 2020. ↩︎
Anagianni C, et al. SLC39A14: a new manganese transporter. Human Molecular Genetics. 2018. ↩︎
Le KS, et al. Zinc transporters in Parkinson's disease. Neurobiology of Disease. 2018. ↩︎
Nazarov V, et al. Zinc transporters in Alzheimer's disease. Journal of Alzheimer's Disease. 2019. ↩︎