Mitochondrial disorders such as Leigh Syndrome and Leber hereditary optic atrophy are rare, but they cause similar symptoms, including vision loss, diabetes, deafness, seizures, and depression. The autosomal recessive disorder Wolfram Syndrome walks and talks like a mitochondrial disorder. The estimated 30,000 people worldwide with the ultra-rare syndrome experience similar symptoms, but something different is at play.

The wolframin ER transmembrane glycoprotein  (WFS1) gene encodes a transmembrane ER (endoplasmic reticulum) protein called wolframin. A mutation in WFS1 is responsible for these typically mitochondria-linked symptoms in people with Wolfram Syndrome. At first glance, this surprised researchers until they discovered that wolframin localizes to the points where the ER and mitochondria touch, called mitochondria-ER associated membranes (MAMs). 

Calcium-rich ER shuttles calcium through MAMs to mitochondria, which activates the ATP-producing proteins in the mitochondria. Mutated wolframin destabilizes MAMs, resulting in fewer contact points between the two organelles and lazier mitochondria. 

So far, researchers haven’t developed an effective therapeutic targeting wolframin, leaving people with Wolfram Syndrome without treatment options. “I imagined that if I could modulate another protein of the MAM, maybe I could correct the cellular deficits and behavioral deficits of the animal models,” said Benjamin Delprat, a molecular neuroscientist from the University of Montpellier and coauthor of a new paper on Wolfram Syndrome.

In their study published in Science Translational Medicine, Delprat and his team used a drug that targets another MAM-localized protein called sigma-1 receptor (S1R) to reverse mitochondrial dysfunction in cells with a wolframin mutation, relieving behavioral symptoms in zebrafish and mouse models of the disease (1).

“The findings are very important and also quite exciting and interesting,” said Fumihiko Urano, a Wolfram Syndrome clinical researcher from Washington University School of Medicine who was not involved in this study. “It’s one of the first articles showing that targeting MAM can improve behavior phenotypes in a mouse model of Wolfram Syndrome.”

The team behind the new study didn’t pick an S1R agonist to test out of thin air. They previously showed that the S1R agonist blarcamesine protected mice against Alzheimer’s disease, a neurodegenerative condition partially caused by mitochondrial dysfunction and increased ER-mitochondrial contact (2). The drug, produced by Anavex Life Sciences, is currently undergoing a phase III clinical trial to test its efficacy in patients with Alzheimer’s disease and a phase II trial in patients with Parkinson’s disease, another neurological condition with etiology linked to misbehaving mitochondria.

Delprat and his team demonstrated that using another S1R agonist, PRE-084, to activate S1R restored the lost contacts between the ER and mitochondria in fibroblasts taken from patients with Wolfram Syndrome. The wolframin-mutation-carrying fibroblasts had fewer contact points between the ER and mitochondria than control fibroblasts, resulting in underactive mitochondria. After treatment with PRE-084, the mitochondria in the Wolfram Syndrome patient-derived fibroblasts had more contact points with the ER and produced more energy as measured by ATP production.

Mice carrying a mutation in wolframin like that found in people with Wolfram Syndrome have difficulty moving, problems with memory and learning, and increased anxiety. The researchers tested if recovery of cellular deficiencies translated to recovery of behavioral phenotypes in an animal model by overexpressing S1R or treating the mice with an S1R antagonist. 

Delprat’s team placed mice in a maze shaped like a capital Y, and the researchers recorded the number of times they entered each arm. Mice generally explore areas searching for food and constantly move to new areas in their quest. Healthy mice usually enter the arm of the maze they haven’t already explored, but mice with memory problems, like the mice carrying the wolframin mutation, repeatedly enter the same arm. When the mutated mice were treated with the S1R agonist, they behaved like healthy mice.

“I remember the exact moment I came to [my student’s] desk and he showed me the result,” Delprat recalled. “We had the proof of concept that [an S1R agonist] may be used to treat Wolfram syndrome.”

Urano was also excited about the drug’s ability to treat anxiety in mice. He sees people with Wolfram Syndrome every week and said that almost all of those patients had anxiety and depression.

“It’s not so easy to control. If targeting the sigma 1 receptor improves behavioral phenotypes, then that’s actually clinically significant,” said Urano. But Urano still wants to know if this drug can treat other problems caused by Wolfram Syndrome such as diabetes and optic atrophy or if it treats only the behavioral symptoms addressed in the paper.

Delprat wants to dive deeper into the role S1R plays in Wolfram syndrome before moving forward with translation into humans. But if the time comes, he’s prepared to take the agonist to the clinic.

“The results are very good and with this solution – activating S1R – maybe we’ll be able to treat Wolfram Syndrome. And that’s the most exciting part,” said Delprat.

References

1. Crouzier, L. et al. Activation of the sigma-1 receptor chaperone alleviates symptoms of Wolfram syndrome in preclinical models. Sci Trans Med  14, 631 (2022).
2. Area-Gomez, E. et al. A key role for MAM in mediating mitochondrial dysfunction in Alzheimer disease. Cell Death and Dis  9, 335 (2018).