The PEX5 gene encodes Peroxisome Biogenesis Factor 5, a critical protein for peroxisome function and cellular homeostasis. PEX5 serves as the primary receptor for peroxisomal matrix protein import, recognizing proteins containing the peroxisomal targeting signal 1 (PTS1) tripeptide sequence. Peroxisomes are essential organelles involved in fatty acid oxidation, reactive oxygen species metabolism, and phospholipid synthesis—all processes critical for neuronal health.
| Property |
Value |
| Gene Symbol |
PEX5 |
| Full Name |
Peroxisome Biogenesis Factor 5 |
| Chromosomal Location |
12p13.31 |
| NCBI Gene ID |
5835 |
| Ensembl ID |
ENSG00000120799 |
| UniProt ID |
P50571 |
| Gene Type |
Protein coding |
| Transcript Length |
3,786 bp (mRNA) |
- Molecular Weight: ~131 kDa
- Subcellular Localization: Cytosol and peroxisomal membrane
- Domain Architecture:
- N-terminal Domain: Binding site for PEX7 ( PTS2 receptor)
- TPR Domain: Tetratricopeptide repeat domain for cargo recognition
- C-terminal PTS1 Binding Pocket: Recognizes the SKL motif
PEX5 is essential for importing proteins into the peroxisome matrix:
- Cargo Recognition: PEX5 binds PTS1-containing proteins (SKL motif) in the cytosol
- Membrane Docking: The PEX5-cargo complex docks at the peroxisomal membrane translocon
- Cargo Translocation: Cargo proteins are translocated into the peroxisome matrix
- PEX5 Recycling: ATP-dependent recycling of PEX5 back to the cytosol by PEX1-PEX6 AAA ATPases
PEX5 is crucial for:
- Formation of new peroxisomes ( proliferation)
- Import of peroxisomal matrix enzymes
- Peroxisome inheritance during cell division
Peroxisomes are essential for:
- β-Oxidation of Very Long-Chain Fatty Acids (VLCFAs): PEX5-dependent import of acyl-CoA oxidases
- Plasmalogen Synthesis: Ether phospholipids critical for myelin
- Bile Acid Synthesis: Cholesterol derivative metabolism
- Catalase Import: Key enzyme for hydrogen peroxide detoxification
- Peroxiredoxins: Antioxidant proteins
- Urate Oxidase: Purine metabolism
PEX5 mutations cause Zellweger syndrome, a severe peroxisome biogenesis disorder:
| Phenotype |
Description |
| Severe Developmental Delay |
Profound intellectual disability |
| Neuronal Migration Defects |
Abnormal brain development |
| Hepatic Dysfunction |
Liver disease, cholestasis |
| Retinal Degeneration |
Vision impairment |
| Hearing Loss |
Sensorineural deafness |
- Infantile Refsum Disease: Milder form with later onset
- Neonatal Adrenoleukodystrophy: Progressive cerebral demyelination
Peroxisomal dysfunction contributes to AD pathogenesis:
- VLCFA Accumulation: Impaired β-oxidation leads to membrane alterations
- Amyloid Metabolism: Peroxisomes regulate amyloid precursor protein processing
- Oxidative Stress: Catalase deficiency increases ROS damage
- Lipid Homeostasis: Altered plasmalogen levels affect neuronal membranes
PEX5 dysfunction affects PD through:
- Mitochondrial-Peroxisomal Crosstalk: Both organelles communicate in quality control
- Pex5 in Dopaminergic Neurons: High vulnerability to peroxisomal defects
- Alpha-Synuclein Clearance: Peroxisomes may participate in protein clearance
- Peroxisomal Function: Impaired in ALS motor neurons
- VLCFA Metabolism: Abnormalities in motor neuron membranes
- Energy Metabolism: Peroxisomes support axonal energy demands
- Peroxisome Numbers: Reduced in HD models
- Metabolic Dysfunction: Altered fatty acid metabolism
- Neuronal Vulnerability: Peroxisomal defects exacerbate degeneration
- AAV-PEX5: Viral vector delivery to restore peroxisomal function
- CRISPR-Cas9: Correct pathogenic PEX5 mutations
- mRNA Therapy: Deliver functional PEX5 mRNA
| Approach |
Mechanism |
Status |
| PPAR agonists |
Enhance peroxisome proliferation |
Clinical trials |
| Antioxidants |
Reduce oxidative stress |
Research |
| VLCFA-lowering drugs |
Reduce toxic metabolites |
Approved for PBD |
PEX5 is expressed throughout the brain:
- Cerebral Cortex: Pyramidal neurons, interneurons
- Hippocampus: CA neurons, dentate gyrus granule cells
- Cerebellum: Purkinje cells, granule cells
- Substantia Nigra: Dopaminergic neurons
- Astrocytes and Oligodendrocytes: Glial peroxisomes
- Dodt G, et al. The PTS1 receptor, PEX5, is a cycling cytosolic protein. J Cell Biol. 1995;131(5):1143-1156
- Francisco T, et al. Peroxisome biogenesis: The peroxisomal importomer. Cell Mol Life Sci. 2017;74(9):1567-1582
- Steinberg S, et al. Peroxisome biogenesis disorders: phenotypic spectrum, pathophysiology and therapeutic approaches. Orphanet J Rare Dis. 2015;10:7
- Waterham HR, Ebberink MS. Genetics and molecular basis of human peroxisome biogenesis disorders. Biochim Biophys Acta. 2012;1822(9):1430-1441