Wolfram syndrome, a rare neurodegenerative disease: from pathogenesis to future treatment perspectives

Abstract

Background: Wolfram syndrome (WS), a rare genetic disorder, is considered the best prototype of endoplasmic reticulum (ER) diseases. Classical WS features are childhood-onset diabetes mellitus, optic atrophy, deafness, diabetes insipidus, neurological signs, and other abnormalities. Two causative genes (WFS1 and WFS2) have been identified. The transmission of the disease takes place in an autosomal recessive mode but autosomal dominant mutations responsible for WS-related disorders have been described. Prognosis is poor, death occurs at the median age of 39 years with a major cause represented by respiratory failure as a consequence of brain stem atrophy and neurodegeneration. The aim of this narrative review is to focus on etiology, pathogenesis and natural history of WS for an adequate patient management and for the discussion of future therapeutic interventions.

Main body: WS requires a multidisciplinary approach in order to be successfully treated. A prompt diagnosis decreases morbidity and mortality through prevention and treatment of complications. Being a monogenic pathology, WS represents a perfect model to study the mechanisms of ER stress and how this condition leads to cell death, in comparison with other prevalent diseases in which multiple factors interact to produce the disease manifestations. WS is also an important disease prototype to identify drugs and molecules associated with ER homeostasis. Evidence indicates that specific metabolic diseases (type 1 and type 2 diabetes), neurodegenerative diseases, atherosclerosis, inflammatory pathologies and also cancer are closely related to ER dysfunction.

Conclusions: Therapeutic strategies in WS are based on drug repurposing (i.e., investigation of approved drugs for novel therapeutic indications) with the aim to stop the progression of the disease by reducing the endoplasmic reticulum stress. An extensive understanding of WS from pathophysiology to therapy is fundamental and more studies are necessary to better manage this devastating disease and guarantee the patients a better quality of life and longer life expectancy.

Keywords: Deafness; Diabetes insipidus; Optic atrophy; Type 1 diabetes; WFS1; WFS2; Wolfram syndrome.

Fig. 1

The ER stress pathway. Under situations of stress, unfolded and misfolded proteins accumulate and recruits BIP to the ER lumen. BIP dissociates from the ER stress sensors IRE1α (inositol-requiring protein 1), ATF6 (activating transcription factor 6) and PERK [protein kinase RNA (PKR)-like ER kinase] and leads to their activation. Upon dimerization and autophosphorylation, IRE1 induces the splicing of XBP1 mRNA for translation of the transcription factor spliced XBP1 protein (sXBP1). XBP1s translocates to the nucleus and controls the transcription of ER-resident chaperones, components of the ERAD machinery and genes involved in lipogenesis. Activated PERK causes the phosphorylation of eukaryotic initiation translation factor 2α (eIF2α), which increases production of activating transcription factor 4 (ATF4). ATF4 then translocates to the nucleus and induces the transcription of many genes required for ER quality control. Activated ATF6 translocates to the Golgi, where it is processed by S1P and S2P proteases. The cleaved-off cytoplasmic domain functions as a transcription factor and induces the expression of ER chaperones and XBP1. ATF6 activity is inhibited by the WFS1 protein, that through the E3 ubiquitin ligase HRD1, is responsible of ATF6 ubiquitin-mediated proteasomal degradation. ER calcium channels, ryanodine receptor (RyR) and inositol triphosphate receptor (IP3R), control efflux of calcium (Ca²⁺) from the ER to the cytosol. Under ER stress activation, these receptors increase the levels of cytosolic calcium and activate the calcium-dependent protease, calpain-2, which promotes cellular apoptosis