Doctoral defence: Marite Punapart "Effects of Valproate and Liraglutide in Rodent Models of Wolfram Syndrome: Emphasis on Transcriptomic Changes in the Renin-Angiotensin-Aldosterone System"

On 30 September Marite Punapart will defend her thesis "Effects of Valproate and Liraglutide in Rodent Models of Wolfram Syndrome: Emphasis on Transcriptomic Changes in the Renin-Angiotensin-Aldosterone System".

Supervisors:
Mario Plaas, University of Tartu
Anton Terasmaa, National Institute of Chemical Physics and Biophysics
Eero Vasar, University of Tartu

Opponent:
Dr Sovan Sarkar, University of Birmingham, (United Kingdom)

Summary:
Wolfram syndrome (WS) is a rare disease caused by mutations in the WFS1 gene, which encodes the protein Wolframin. The disease is characterized by insulin-dependent diabetes, progressive optic nerve atrophy, diabetes mellitus and hearing loss, which develop on average during the first twenty years of life. In addition, psychiatric disorders and several other neurological complications may accompany it. There is currently no effective treatment for WS, but several drugs already in clinical use are being investigated to slow the course of WS. These include the antiepileptic valproate and the antidiabetic liraglutide.

The first half of this thesis focused on characterizing the effects of valproate in a mouse model of WS. It was found that valproate affected genes mainly related to oxidative stress, fat metabolism and circadian rhythm in the liver tissue of WS mice. The most affected was Ppar𝛽/𝛿, which also plays an important role in glucose metabolism. When testing the effect of valproate on blood sugar in WS mice, it was found that a single administration of the drug improved blood sugar metabolism, while long-term treatment had no effect.

In the second half of the thesis, the importance of WFS1 and the effects of valproate and liraglutide on the renin-angiotensin-aldosterone system (RAAS) were investigated in a rat model of WS. The RAAS, like WFS1, has been linked to structures associating mitochondria and endoplasmic reticulum that are important for neuron survival. Gene expression of the key RAAS receptors angiotensin II type 2 and bradykinin B1 was significantly decreased in WS rats. In addition, lower aldosterone and higher bradykinin levels were observed. Low aldosterone levels have recently been directly linked to WFS1 deficiency. Valproate and liraglutide failed to normalize the gene expression levels, but increased aldosterone and decreased bradykinin levels in those rats.

Although physiological manifestations suggestive of RAAS disturbance are not apparent in WS rats, the RAAS is evidently dysregulated at the transcriptional level. At the same time, it seems that its functioning is strongly affected by stress. Disturbed RAAS can exacerbate inflammatory processes and oxidative stress, thereby accelerating the course of the disease, so it’s importance in WS cannot be underestimated.