Anavex Life Sciences Corp (AVXL)

[DFRAI]

Wolfram syndrome (WS) is a rare genetic disease caused by mutations in the wolframin gene (WFS1),
resulting in the more prevalent type I WS, or in the CDGSH iron sulfur-containing domain 2 gene (CISD2),
resulting in the rarer type II WS
1,2
. The primary symptoms of Wolfram syndrome (insulin-dependent
diabetes mellitus, optic atrophy, diabetes insipidus and hearing loss) can emerge at different ages and
change at different rates
3–5
. The current treatment of Wolfram syndrome is symptomatic and supportive.
Diabetes insipidus is managed by treatment with vasopressin and diabetes mellitus by insulin; recent
case reports
6,7 suggest a benefit of glucagon-like peptide-1 (GLP-1) receptor agonists. However, so far,
there is no treatment available for the neurological manifestations of WS. Relatively slow progress in WS
treatment is related to a lack of knowledge of which cellular mechanisms are responsible for neurological
symptoms.
Both WS genes encode transmembrane endoplasmic reticulum proteins
5 and it is widely acknowledged
that the primary defect in WS lies also in the ER
8–11
. However, recent discoveries indicate that while the
primary defect may indeed originate in the ER, the key factor driving the disease progression might lie
within the mitochondria. Our previous research has demonstrated that WFS1 downregulation in cortical
neurons disturbed mitochondrial dynamics and suppressed mitochondrial ATP production
10
. Angebault
et al.
12
further demonstrated in WS patient fibroblasts that loss of WFS1 reduced the number of
mitochondrial contact sites with the ER (MAMs), decreased Ca
2+ uptake by mitochondria, and decreased
mitochondrial respiration. Reduction in MAMs, mitochondrial respiration, and ATP production was then
also observed in WS patient-derived neuronal cells
13
. Furthermore, most recent findings by Crouzier et
al.
14 suggest that the ER-to-mitochondria Ca
2+ flux could be corrected with Sigma-1 receptor agonist,
improving mitochondrial physiology in patient fibroblasts and alleviating the behavioral symptoms
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observed in zebrafish and mouse models of the disease. Notably, mutations in CISD2 are also associated
with mitochondrial abnormalities
15–17
.
https://assets.researchsquare.com/files/rs-3385750/v1/4f503ae7-a968-4ed7-935e-81af4046feed.pdf?c=1697488714