Zellweger Syndrome: Ghost Peroxisomes and the Deadly Accumulation of VLCFAs

Zellweger Syndrome is a rare genetic condition. In this disease there are defects in peroxisomes, which are vital organelles that help metabolize fatty acids and detoxify harmful substances.

What are peroxisomes:

Peroxisomes are membrane-bound organelles that play a key role in various metabolic activities, such as the β-oxidation of very long-chain fatty acids (VLCFAs), the production of plasmalogens needed for myelin formation, and the detoxification of metabolites.

Why VLCFAs processing require Peroxisomes

Mitochondria cannot break down fatty acids with 22 or more carbons. Peroxisomes exclusively carry out the initial steps of β-oxidation of very long-chain fatty acids (VLCFAs). These steps shorten VLCFAs, producing smaller fatty acids that mitochondria can further degrade.

Enzymes for VLCFAs initial β-oxidation

Initial β-oxidation of VLCFAs in peroxisomes require three essential enzymes.

1) Acyl-CoA Oxidase 1 (ACOX1),

2) D-Bifunctional Protein (DBP), and

3) Peroxisomal Thiolase (ACAA1).

Cells make these three peroxisomal proteins in the cytoplasm. The cell must then import them into the peroxisome. A Peroxisomal Targeting Signal (PTS) directs these proteins to their destination inside the organelle.

PTS1 → SKL (Ser-Lys-Leu) sequence at C-terminal

PTS2 → N-terminal nonapeptide sequence

Special proteins called Peroxins (PEX proteins) recognize these targeting signals and import proteins into peroxisome.

The PTS1 Tag & the PEX5 Courier

• Enzymes like Acyl-CoA Oxidase (ACOX1) and Thiolase have a simple “PTS1” tag at their tail end. Think of PEX5 as a specialized courier that scans for this specific tag, grabs the enzyme, and shuttles it to the peroxisome.

The PTS2 Tag & the Partnered Couriers

• The D-Bifunctional Protein (DBP) uses a more complex “PTS2” tag located at its head. A different courier, PEX7, is assigned to this tag. However, PEX7 cannot work alone; it must partner with the PEX5 courier to successfully deliver its enzyme.

In essence, PEX5 is the master coordinator, directly handling PTS1 deliveries

Protein Transport Mechanism

Proteins meant for peroxisomes are made in the cytoplasm and need specific targeting signals (PTS1 and PTS2) for transport. PEX proteins, like PEX5 and PEX7, serve as couriers. PEX5 protein identify these signals (PTS1 and PTS2) and help import enzymes into peroxisomes.

PEX5 is especially crucial for transporting enzymes with the PTS1 tag, while PEX7 collaborates with PEX5 for those with the PTS2 tag.

Stepwise Transport of Enzymes by PEX5

The transport of enzymes, such as those needed for VLCFA β-oxidation, is handled by PEX5, the primary cytosolic receptor.

1. Cargo Binding (Cytosol): The PEX5 protein (the courier) patrols the cytosol and recognizes the specific “address tag” known as PTS1 (Peroxisomal Targeting Signal 1) located on the tail of the target enzymes (the cargo). PEX5 binds tightly to the enzyme.
2. Docking (Peroxisome Membrane): The entire PEX5-enzyme complex travels to the peroxisome membrane and binds to a specific receptor complex, initiating the formation of a temporary membrane pore, or translocator.
3. Translocation (Import): PEX5 inserts into the membrane and guides the enzyme cargo across the membrane and into the peroxisome’s interior (the lumen). The cargo is then released inside the peroxisome.
4. Conformational Change: After releasing the enzyme, PEX5 remains temporarily stuck in the peroxisome membrane, waiting to be retrieved.

PEX1/PEX6 Mediated Recycling of PEX5

Once PEX5 is stuck in the membrane, it must be removed and returned to the cytosol so it can pick up the next enzyme load. This is the job of the PEX1/PEX6 ATPase complex.

1. Ubiquitination: Another peroxin, PEX2, PEX10, or PEX12 (part of the membrane complex), attaches a small protein tag called ubiquitin to the stuck PEX5. This acts as a signal for recycling.
2. Recognition by PEX1/PEX6: The PEX1/PEX6 complex, a strong ATPase (a machine that uses ATP for energy), recognizes the ubiquitinated PEX5.
3. Extraction (Recycling): PEX1 and PEX6 use the energy from ATP hydrolysis to physically pull the PEX5 receptor out of the peroxisome membrane and back into the cytosol.
4. Re-entry into Cycle: Once released, the PEX5 protein is ready to pick up a new enzyme cargo and repeat the import cycle.

Zellweger Syndrome:

Zellweger Syndrome is a rare autosomal recessive disorder caused by mutations in PEX genes, most often PEX1 or PEX6. These mutations disrupt the recycling of the import receptor PEX5, preventing key enzymes (such as acyl-CoA oxidase and multifunctional enzyme type 2) from entering the peroxisome. As a result, peroxisomes become nonfunctional “ghosts.” The major biochemical defect is the accumulation of very long-chain fatty acids (VLCFAs) in blood and tissues. High VLCFA levels impair neuronal migration, myelination, and synapse formation, and also damage the liver, kidneys, and adrenal glands, leading to the severe developmental, neurological, and metabolic symptoms of Zellweger Syndrome.

In Short:

👉 In Zellweger syndrome, mutations in PEX genes (like PEX1, PEX5, PEX6) prevent peroxisomal protein import.

• Result: peroxisomes are “empty” (called ghost peroxisomes).