Abstract

Marinesco-Sjögren syndrome (MSS) is a rare autosomal-recessive genetic disorder for which there is no cure. Patients present with ataxia, muscle weakness, and cataracts, although many other symptoms may be present, including mental retardation, short stature, and nystagmus. From a molecular perspective, a mutation in the SIL1 gene has been shown to cause MSS; however, the disease initiator has not yet been identified in many cases. SIL1 encodes an endoplasmic reticulum (ER) nucleotide exchange factor required to release adenosine diphosphate and folded proteins from the chaperone-binding immunoglobulin protein. Loss of SIL1 function impairs ER protein folding, triggering the unfolded protein response (UPR) to restore ER homeostasis. However, protracted UPR is a major factor in Purkinje cell degeneration and myopathy. Depending on the timeliness of its administration, a treatment for MSS could cure the syndrome or substantially improve muscle strength and halt the progression of ataxia. To date, we have accumulated sufficient information to implement preclinical treatments partly due to the knowledge obtained in animal models representative of the human syndrome. Inhibition of ER PRK-like kinase arms of UPR improved the motor performances of a woozy mouse model of MSS, delayed Purkinje degeneration, and reduced skeletal muscle alterations. However, the beneficial effect of this treatment diminished over time and was toxic to the pancreas. Another potential approach was experimented on immortalized lymphoblasts from patients. In this case, the chemical chaperone tauroursodeoxycholic acid reduced apoptosis of lymphoblasts. Taking cues from other recessive diseases, it would also be possible to reintroduce wild-type SIL1 to restore the missing function, but no such evidence has been reported so far. In conclusion, although not yet available, there is good guidance on approaching the treatment of MSS.