International Wolfram Syndrome Symposium
11 th WOLFRAM SYNDROME international researcher’s symposium on 3rd & 4th June is held in Berkshire, England.
Dr Mario Plaas presents “Early Axonal Pathology in WFS1 Deficiency Suggests a Broader Role for WFS1 in Neurodegeneration”.
Wolfram syndrome type 1 (WS1) is a rare neurodegenerative disorder caused by pathogenic variants in WFS1, which encodes an endoplasmic reticulum (ER) transmembrane protein. WFS1 has been primarily linked to calcium (Ca²⁺) homeostasis, mitochondrial function, and ER stress responses. However, the intracellular and tissue-level pathological changes caused by Wfs1 loss, particularly in neuronal tissue, remain poorly understood.
In our previous work, we demonstrated that loss of Wfs1 function disrupts the balance between GABA and glutamate, leading to degenerative changes in parvalbumin-positive (PV+) interneurons and the surrounding perineuronal net. Notably, these alterations occur despite the absence of detectable WFS1 expression in PV+ interneurons, suggesting indirect or circuit-level mechanisms of pathology.
In this presentation, we provide the first evidence that the role of WFS1 in the development of neurodegenerative pathology may be substantially broader than previously assumed. We show for the first time that the brains of Wfs1 loss-of-function rats contain distinct axonal aggregates that are already detectable at 3 months of age, with features reminiscent of axonal pathology described in Alzheimer’s disease. Importantly, these aggregates increase markedly with age, indicating progressive axonal and/or axonal cytoskeletal damage, which may result in protein accumulation and impaired transport of proteins and neurotransmitters.
The exact nature of these aggregates remains unclear. They may represent either a pathological process or a cellular rescue response. Nevertheless, our findings identify early and progressive axonal pathology as a previously unrecognized feature of WFS1 deficiency and suggest that WFS1 may have a broader role in neurodegenerative disease mechanisms than currently appreciated.
