Systemic inflammation and neurodegeneration in a mouse model of multiple sulfatase deficiency

Abstract

Sulfatases are involved in several biological functions such as degradation of macromolecules in the lysosomes. In patients with multiple sulfatase deficiency, mutations in the SUMF1 gene cause a reduction of sulfatase activities because of a posttranslational modification defect. We have generated a mouse line carrying a null mutation in the Sumf1 gene. Sulfatase activities are completely absent in Sumf1 ؊/؊ mice, indicating that Sumf1 is indispensable for sulfatase activation and that mammals, differently from bacteria, have a single sulfatase modification system. Similarly to multiple sulfatase deficiency patients, Sumf1 ؊/؊ mice display frequent early mortality, congenital growth retardation, skeletal abnormalities, and neurological defects. All examined tissues showed progressive cell vacuolization and significant lysosomal storage of glycosaminoglycans. Sumf1 ؊/؊ mice showed a generalized inflammatory process characterized by a massive presence of highly vacuolated macrophages, which are the main site of lysosomal storage. Activated microglia were detected in the cerebellum and brain cortex associated with remarkable astroglyosis and neuronal cell loss. Between 4 and 6 months of age, we detected a strong increase in the expression levels of inflammatory cytokines and of apoptotic markers in both the CNS and liver, demonstrating that inflammation and apoptosis occur at the late stage of disease and suggesting that they play an important role in both the systemic and CNS phenotypes observed in lysosomal disorders. This mouse model, in which the function of an entire protein family has been silenced, offers a unique opportunity to study sulfatase function and the mechanisms underlying lysosomal storage diseases.apoptosis ͉ macrophages ͉ sulfatase modifying factor 1

Molecular analysis ofSUMF1 mutations: stability and residual activity of mutant formylglycine-generating enzyme determine disease severity in multiple sulfatase deficiency

“…This patient showed neonatal disease onset with rapid progression (personal data). The majority of SUMF1 knock out mice, generated recently, die within the first month of age [Settembre et al, 2007]. In these mice sulfatase activities are completely absent.…”

SUMF1 mutations affecting stability and activity of formylglycine generating enzyme predict clinical outcome in multiple sulfatase deficiency

“…22,23 Null mutations result in the complete absence of sulfatase activities, as shown in a SUMF1 gene-trap mouse. 24 Expression of FGE carrying MSD patient mutations in SUMF1-deficient mouse fibroblasts results in detectable, although extremely low sulfatase activities, underlining that MSD is a monogenetic disease caused by hypomorphic mutations. 25 Until now, more than 30 different SUMF1 mutations were found, most of which are missense mutations.…”

A non-conserved miRNA regulates lysosomal function and impacts on a human lysosomal storage disorder

“…M aintaining the required biological ratio of sulfated versus non-sulfated molecules in the cell is critical for several biological processes ranging from fetal development and hormone metabolism to growth factor signalling, bone remodelling and degradation of macromolecules [1][2][3][4][5] . Thus, sulfate homeostasis is highly dynamic and tightly regulated by multiple enzymes including a large family of sulfatase enzymes that hydrolyse sulfate esters from many substrates, including sulfolipids, steroid sulfates and glycosaminoglycans (GAGs) 6 .…”

“…The clinical picture of MSD is complex and combines the symptoms of individual sulfatase deficiencies including severe neurodegeneration, skeletal abnormalities, facial dysmorphism, organomegaly and premature death 7 . Recent studies, including the generation of the Sumf1 À / À mouse, have elucidated important links between the pathogenesis of MSD and inhibition of the autophagy pathway 4,9 .…”

“…Free and proteoglycan-bound GAG chains are highly modified by sulfation and are the main substrates for lysosomal sulfatases. Hence, GAGs are the primary substrate type seen to accumulate in multiple tissues from the Sumf1 À / À MSD mouse model as well in MSD patients 4,33 . To test whether SUMF1 and thereby sulfatase reactivation by miR-95 inhibition could affect cellular levels of sulfated GAGs, we extracted and quantified total sulfated GAGs from MSD fibroblasts.…”