Wolfram Syndrome: A Case Report and Review of Clinical Manifestations, Genetics Pathophysiology, and Potential Therapies

Figure 1

Hypothesized molecular pathophysiology of WS. Under situations of stress, such as hyperglycaemia and elevated free fatty acids levels, unfolded and misfolded proteins accumulate [31]. Endoplasmic reticulum (ER) transmembrane proteins sense the stress and activate the unfolded protein response (UPR) [31]. The UPR may culminate in either an adaptive response which decreases the workload on the ER or a maladaptive response (as occurs in chronic hyperglycaemia or WS) which culminates in cellular apoptosis [31]. Ⓐ In healthy cells, the transmembrane protein (WFS1) complexes with activating transcription factor-6 (ATF-6) and directs ATF-6 to ubiquitin-mediated proteasome degradation [31]. This serves to negatively regulate the UPR [31]. In WFS1 deficient cells ATF-6 is no longer under negative inhibition and is permitted to constitutively activate genes that promote cellular apoptosis and decrease insulin gene expression [31]. Ⓑ ER calcium channels, such as the ryanodine receptor (RyR), but most importantly the inositol triphosphate receptor (IP3R), permit efflux of calcium from the ER to the cytosol [16, 28]. It is believed that increased cytoplasmic calcium levels activate the calcium-dependent protease, calpain-2, which promotes cellular apoptosis [16, 34]. Potential therapeutic targets include molecules which inhibit calcium efflux from the ER, such as dantrolene, via inhibition of the RyR [35], and rapamycin and pioglitazone, via inhibition of IP3R [34]. In neuronal WS models, cytosolic calcium appears to be increased under resting conditions and reduced under stimulated conditions [28]. This disruption in cytoplasmic calcium homeostasis also dysregulates mitochondrial dynamics which leads to lower ATP levels [28]. This is thought to hinder neuronal development and survival [28]. Ⓒ Under periods of ER stress, pancreatic ER kinase (PERK), a transmembrane ER protein, becomes activated and through the action of protein kinase A (PKA) and cyclic-AMP (cAMP) results in the phosphorylation of translation initiation factor 2α (eIF2α) (not shown) [36]. This in turn results in increased production of activating transcription factor 4 (ATF4) which increases the expression of genes for ER stress recovery [31, 36, 37]. Furthermore, phosphorylated eIF2α leads to decreased overall protein synthesis and therefore to reduction in the ER protein load (not shown) [36]. Glucagon-like peptide-1 receptor (GLP-1R) activation, acting downstream of PERK, decreases the phosphorylation of eIF2α via the PKA/cAMP pathway, in order to ameliorate the decrease in protein synthesis that would otherwise occur (not shown) [36, 37]. This mechanism of action of GLP-1R activity facilitates a faster resumption of protein synthesis following ER stress (not shown) [36, 37].