Journal News

Sphingolipid secrets of wound healing

Elizabeth Stivison
Feb. 9, 2022

We need the right kinds of sphingolipids in our bodies. 

Sphingolipids are a class of lipids containing sphingosine, a long hydrocarbon chain attached to a head group derived from an amino acid — humble molecules that researchers are finding have many roles in the cell.

Courtesy of Thorsten Hornemann
A scratch assay is shown immediately after the scratch was created (top) and 10
hours later (bottom). On bottom left, cells were exposed to canonical sphingolipids;
on bottom right, cells were exposed to 1-deoxy-sphingolipids.

An example of the havoc incorrect sphingolipid metabolism can wreak is the rare disease hereditary sensory neuropathy type 1, or HSAN1, which is caused by altered sphingolipid synthesis. People with HSAN1 experience severe peripheral neuropathy, a progressive loss of sensation in the extremities.

Thorsten Hornemann at the University Hospital Zurich has been studying sphingolipids in the context of such diseases for more than a decade. Hornemann and colleagues discovered that people with HSAN1 have a mutation in the enzyme that catalyzes the first step of sphingolipid synthesis, greatly overproducing an atypical type of sphingolipid called 1-deoxy-sphingolipid, or 1-deoxy-SL, that uses glycine or alanine in its synthesis instead of the canonical serine. This work showed that 1-deoxy-SLs are neurotoxic, potentially explaining the mechanism of HSAN1 neuropathy.

HSAN1 is estimated to affect only about two in every million people, but Type 2 diabetes, which has been diagnosed in about half a billion people worldwide, can cause almost identical symptoms.

A missing puzzle piece of this coincidence slid into place when Hornemann’s lab discovered that people with diabetes also have increased 1-deoxy-SLs, like HSAN1 patients. They then showed that lowering the levels of 1-deoxy-SLs improves neuropathy in diabetic rats.

There’s more than neuropathy though.

“HSAN1 patients frequently develop recurring and bad-healing wounds and ulcers,” Hornemann wrote in an email. “Since the patients also have no feeling for pain, they often don’t have proper wound protection or care, which makes the injuries progressively worse.”

The most severe injuries sometimes require amputation, and the same thing can happen in diabetes. 

Hornemann’s group had observed that 1-deoxy-SLs alter the cytoskeleton, which gave them a new hypothesis: “We realized that (the cytoskeleton) might not only be important for neurons to maintain their structural integrity, but also for the wound healing process itself,” he explained. “The healing of a skin wound requires a highly coordinated migration of cells.”

Sphingosine is the hallmark component of sphingolipids.

This depends on the cytoskeleton and could be altered directly by 1-deoxy-SLs.

In their recent work published in the Journal of Lipid Research, Hornemann’s lab investigated this hypothesis by modeling wound healing in cell culture. The team grew plates of cells and then scratched the surface of the cell-covered plate, leaving a gap where cells were scratched away. They then measured how well cells migrated over the gap and filled it back in. Cells that were exposed to a higher level of 1-deoxy-SLs had a harder time migrating and filling in the gap, providing an explanation for the wound healing defect seen in HSAN1 and diabetes.

The lab’s work highlights two possible routes for treatment. In the current paper, it turned out that blocking the enzyme that interconverts different species of 1-deoxy-SL prevented the wound-healing defect. They also had shown previously that HSAN1 symptoms can be relieved by supplementation with serine, which pushes the cellular equilibrium away from 1-deoxy-SL toward canonical sphingolipids.

Since it appears that the same mechanism is behind the wound healing and neuropathy in diabetes, Hornemann suggests, “the same approach might also suppress 1-deoxySL formation in patients with diabetes and could be a therapeutic option.”

Enjoy reading ASBMB Today?

Become a member to receive the print edition four times a year and the digital edition monthly.

Learn more
Elizabeth Stivison

Elizabeth Stivison is a careers columnist for ASBMB Today and an assistant laboratory professor at Middlebury College.

Get the latest from ASBMB Today

Enter your email address, and we’ll send you a weekly email with recent articles, interviews and more.

Latest in Science

Science highlights or most popular articles

Computational tool helps scientists create novel bug sprays
Journal News

Computational tool helps scientists create novel bug sprays

May 20, 2025

Rapid discovery of mosquito repellent compounds is enabled through a novel screening platform that combines both computational modeling and functional screening.

Meet Lan Huang
Interview

Meet Lan Huang

May 19, 2025

Molecular & Cellular Proteomics associate editor uses crosslinking mass spec to study protein–protein interactions to find novel therapeutics.

Influenza gets help from gum disease bacteria
Journal News

Influenza gets help from gum disease bacteria

May 15, 2025

Scientists discover that a protease from Porphyromonas gingivalis enhances viral spread. Read more about this recent Journal of Biological Chemistry paper.

How bacteria fight back against promising antimicrobial peptide
Journal News

How bacteria fight back against promising antimicrobial peptide

May 15, 2025

Researchers find a mutation in E. coli that reduces its susceptibility to a potential novel antibiotic. Read more about this recent Journal of Biological Chemistry paper.

New clues reveal how cells respond to stress
Journal News

New clues reveal how cells respond to stress

May 15, 2025

Redox signaling protein may help regulate inflammasome and innate immune activation. Read more about this recent Journal of Biological Chemistry paper.

Innovative platform empowers scientists to transform venoms into therapeutics
Journal News

Innovative platform empowers scientists to transform venoms into therapeutics

May 13, 2025

Scientists combine phage display and a “metavenome” library to discover new drugs that bind clinically relevant human cell receptors. Read about this recent Molecular & Cellular Proteomics paper.