| Property | Value |
|---|---|
| Gene Symbol | PEX10 |
| Full Name | Peroxisome Biogenesis Factor 10 |
| Chromosomal Location | 1p36.32 |
| NCBI Gene ID | 5199 |
| OMIM ID | 614863 |
| Ensembl ID | ENSG00000103356 |
| UniProt ID | O00391 |
| Encoded Protein | Peroxin-10 |
| Associated Diseases | Zellweger Spectrum Disorders, Peroxisome Biogenesis Disorder, Autism Spectrum Disorder, Alzheimer's Disease, Parkinson's Disease |
PEX10 (Peroxisome Biogenesis Factor 10) encodes a critical peroxin essential for peroxisome biogenesis and peroxisomal matrix protein import. Peroxisomes are membrane-bound organelles that play vital roles in fatty acid oxidation, plasmalogen synthesis, hydrogen peroxide metabolism, and bile acid synthesis[1]. PEX10 functions as a RING finger ubiquitin ligase that recognizes peroxisomal matrix proteins with defects in peroxisomal targeting signals and facilitates their retrotranslocation to the cytosol for quality control degradation.
Mutations in PEX10 cause Zellweger spectrum disorders (ZSD), a group of severe peroxisome biogenesis disorders characterized by profound developmental delay, craniofacial abnormalities, hepatomegaly, and progressive neurodegeneration[2][3]. Beyond these rare genetic disorders, PEX10 and peroxisomal function have been increasingly implicated in more common neurodegenerative conditions, including Alzheimer's disease (AD) and Parkinson's disease (PD)[4][5].
| Feature | Details |
|---|---|
| Chromosome | 1p36.32 |
| Strand | Plus strand |
| Exons | 4 |
| Transcript length | 1,536 bp coding region |
| Protein length | 335 amino acids |
| RefSeq | NM_001374497 |
PEX10 is highly conserved across eukaryotes:
| Species | Identity | Notes |
|---|---|---|
| Human | Reference | Full length |
| Mouse | 92% | Functional conservation |
| Zebrafish | 78% | Peroxisome biogenesis |
| Drosophila | 65% | Basic function preserved |
| S. cerevisiae | 48% | Pex10p ortholog |
| A. thaliana | 54% | Plant peroxin |
PEX10 belongs to the peroxin family involved in peroxisome biogenesis:
| Peroxin | Function | Disease if mutated |
|---|---|---|
| PEX1 | AAA-ATPase, peroxisome proliferation | ZSD (most common) |
| PEX2 | Peroxisomal membrane protein | ZSD |
| PEX5 | PTS1 receptor, protein import | ZSD |
| PEX6 | AAA-ATPase, import | ZSD |
| PEX10 | RING finger E3 ligase | ZSD |
| PEX12 | RING finger E3 ligase | ZSD |
| PEX13 | Docking factor | ZSD |
PEX10 is a multi-domain protein with distinct functional regions:
| Domain | Amino Acids | Function |
|---|---|---|
| N-terminal | 1-30 | Cytoplasmic exposure, initial protein interactions |
| Membrane anchor | 31-60 | peroxisomal membrane insertion |
| RING finger | 61-150 | E3 ubiquitin ligase activity, substrate recognition |
| Central loop | 151-250 | Protein-protein interactions |
| C-terminal | 251-335 | Quality control function |
The RING finger domain (C3H2C3-type) coordinates two zinc ions and is essential for PEX10's E3 ubiquitin ligase activity:
| Partner | Interaction Type | Functional Consequence |
|---|---|---|
| PEX2 | Complex | E3 ubiquitin ligase complex formation |
| PEX12 | Complex | RING finger complex, substrate recognition |
| PEX5 | Substrate | Import receptor for PTS1 proteins |
| PEX3 | Docking | Peroxisomal membrane anchoring |
| PEX19 | Docking | Peroxisomal targeting |
PEX10 plays a central role in peroxisome biogenesis[6]:
The peroxisomal targeting signal (PTS1) pathway:
Peroxisomes are essential for several lipid metabolic pathways:
| Pathway | Substrate | Product | Clinical Relevance |
|---|---|---|---|
| β-oxidation | Very long-chain fatty acids (VLCFAs) | Acetyl-CoA | Elevated in ZSD, AD |
| Plasmalogen synthesis | Fatty alcohols | Plasmalogens | Myelin deficiency |
| Phytanic acid oxidation | Phytanic acid | Pristanic acid | Refsum disease |
| Bile acid synthesis | C27-sterols | Primary bile acids | Liver dysfunction |
Peroxisomes contain key antioxidant enzymes:
Plasmalogens (ether phospholipids) are essential for:
PEX10 shows widespread expression with highest levels in peroxisome-rich tissues:
| Tissue | Expression Level | Notes |
|---|---|---|
| Liver | Very high | Primary peroxisome function |
| Kidney | High | Peroxisomal metabolism |
| Brain | High | Neurons and glia |
| Skeletal muscle | Moderate | Energy metabolism |
| Heart | Moderate | Lipid metabolism |
| Lung | Low-Moderate | Metabolic function |
Within the central nervous system:
| Region | Expression | Cell Type |
|---|---|---|
| Cerebral cortex | High | Pyramidal neurons |
| Hippocampus | High | CA neurons, dentate gyrus |
| Cerebellum | High | Purkinje cells |
| Basal ganglia | Moderate | Medium spiny neurons |
| White matter | High | Oligodendrocytes |
PEX10 mutations cause a severe form of ZSD[7][2:1]:
| System | Manifestation |
|---|---|
| Neurological | Profound intellectual disability, hypotonia, seizures, developmental regression |
| Vision | Retinal degeneration, optic atrophy, cataracts |
| Hearing | Sensorineural hearing loss |
| Craniofacial | Characteristic dysmorphic features, high forehead, epicanthal folds |
| Hepatic | Hepatomegaly, cholestasis, liver dysfunction |
| Skeletal | Calcific stippling, vertebral anomalies |
| Mutation Type | Severity | Phenotype |
|---|---|---|
| Null/nonsense | Severe | Classic Zellweger |
| Missense (RING) | Moderate | Neonatal ZSD |
| Missense (other) | Mild | Adult ZSD |
| Compound heterozygous | Variable | Spectrum |
Peroxisomal dysfunction is increasingly recognized in AD pathogenesis[4:1][8]:
| Finding | Evidence |
|---|---|
| Peroxisome number | Decreased in AD brain |
| Catalase activity | Reduced in AD cortex |
| VLCFAs | Elevated in AD plasma and brain |
| Plasmalogens | Decreased in AD white matter |
| PEX10 expression | Altered in AD |
Peroxisomal dysfunction has been implicated in PD[5:1]:
| Finding | Reference |
|---|---|
| Peroxisome loss in PD substantia nigra | Ibanez et al., 2022 |
| PEX5 alterations in PD models | Published |
| VLCFAs elevated in PD CSF | Conference reports |
| Phytanic acid metabolism impaired | Case studies |
PEX10 and peroxisomal function have been linked to ASD:
| Evidence | Details |
|---|---|
| Genetic | Rare PEX10 variants in ASD patients |
| Biochemical | Altered VLCFAs in some ASD cases |
| Lipid metabolism | Peroxisomal function in synaptic membranes |
| Energy | Peroxisomal β-oxidation in neurons |
Peroxisomal function declines with age[8:1]:
| Strategy | Compound | Status |
|---|---|---|
| PPARα agonists | Fibrates | FDA-approved, peroxisome proliferation |
| VLCFA reduction | Lorenzo's oil | Available for X-ALD |
| Plasmalogen precursors | DHA-ether phospholipids | Clinical trials |
| Antioxidants | Catalase mimetics | Preclinical |
PEX10 and peroxisomal markers:
| Marker | Utility |
|---|---|
| Plasma VLCFAs | Diagnostic, monitoring |
| Red blood cell plasmalogens | Disease progression |
| Fibroblast peroxisome function | Diagnostic |
| PEX10 expression | Research |
| Model | Phenotype | Relevance |
|---|---|---|
| Pex10-/- | Embryonic lethal | Severe peroxisome loss |
| Pex10+/- | Partial peroxisome dysfunction | Mild ZSD model |
| Conditional KO | Brain-specific | Neurodegeneration studies |
| Method | Application |
|---|---|
| Immunohistochemistry | Tissue localization |
| Western blot | Protein expression |
| Catalase activity | Functional assessment |
| EM | Peroxisome morphology |
| VLCFA quantification | Metabolic status |
| System | Use |
|---|---|
| Patient fibroblasts | Diagnostic, mechanism |
| Mouse models | In vivo studies |
| Yeast models | Basic mechanism |
| iPSC neurons | Human disease |
| Pathway | Modulation |
|---|---|
| PPARα signaling | Peroxisome proliferation |
| mTORC1 | Coordinate metabolism |
| Antioxidant response | Nrf2 pathway |
| Lipid synthesis | SREBP regulation |
| Organelle | Interaction |
|---|---|
| Mitochondria | β-oxidation coordination |
| ER | Lipid synthesis |
| Lysosomes | Degradation pathways |
| Nucleus | Transcriptional regulation |
Watkins et al. Peroxisomes and neurodegeneration. Nat Rev Neurosci. 2015. ↩︎
Steinberg et al. PEX10 mutations cause peroxisome biogenesis disorder. Hum Mol Genet. 2004. ↩︎ ↩︎
Ebberink et al. Peroxisome biogenesis disorders. J Pediatr. 2012. ↩︎
van Vliet et al. Peroxisome dysfunction in Alzheimer's disease. Acta Neuropathol. 2021. ↩︎ ↩︎
Ibanez et al. Peroxisomal dysfunction in Parkinson's disease. Mov Disord. 2022. ↩︎ ↩︎
Stehlik et al. Peroxisome biogenesis factors PEX2 and PEX10. J Cell Biol. 2020. ↩︎
Hille et al. PEX10 mutations in additive inheritance. Am J Hum Genet. 2023. ↩︎
Federico et al. Peroxisomal metabolism in aging and neurodegeneration. Aging Cell. 2023. ↩︎ ↩︎