Identification of new markers for neurodegeneration process in the mouse model of Sly disease as revealed by expression profiling of selected genes

Abstract

Sly disease (MPS VII) is an autosomal-recessive lysosomal storage disorder resulting from beta-glucuronidase deficiency, which is characterized by a severe neurological impairment. MPS VII mice accumulate undegraded glycosaminoglycans and mimic the human neurodegenerative disorder, thus appearing to be an excellent tool to delineate disease pathogenesis. The relationship between abnormal glycosaminoglycan storage and neurodysfunction is not yet well understood, but inflammatory components can be involved, as in several neurological lysosomal disorders. Inflammatory biomarkers are thus good candidates to evaluate the neurodegeneration state of the disease. By using quantitative polymerase chain reaction, we have compared the expression of selected genes of normal and MPS VII cerebral tissues, focusing on inflammation and apoptosis-related genes. The gene expression was evaluated in various brain regions throughout the lifetime of the animals. We have identified a specific expression profile for 27 genes, which was strongly marked in the central nervous system posterior region. Finally, new Sly disease markers were characterized that reflect neurological deterioration state, and that can be used in preclinical follow-up studies.

CNS-directed gene therapy for the treatment of neurologic and somatic mucopolysaccharidosis type II (Hunter syndrome)

“…When MPSII mice were analyzed at 6 months of age, i.e., 4 months after administration of AAV9-Ids vectors, the content of GAGs, the general and ultrastructural aspect, and the size and function of brain lysosomes were all corrected in treated animals, but these had worsened in nontreated MPSII animals or those receiving noncoding AAV9-Null vectors. Two-month-old untreated MPSII mice also showed pronounced astrocytosis and microgliosis throughout the brain, a hallmark finding in different animal models of mucopolysaccharidoses that present with neurodegeneration (38,40,52,54,(68)(69)(70) and in Hunter syndrome patients (47,48). The effects of AAV9-mediated IDS gene transfer on the transcriptional signature and histological findings associated with microglial activation in 6-month old animals were quite striking and were in agreement with our previous observations in MPSIIIB mice (40).…”

Involvement of the Toll-like receptor 4 pathway and use of TNF-α antagonists for treatment of the mucopolysaccharidoses

“…3F). TNF-α is an important downstream mediator of TLR4, and several investigators have recently shown that TLR4 activation and/or TNF-α has important pathogenic effects in the brains of MPS mouse models (6,25). We therefore examined the locomotor behavior of the DKO mice using an accelerating rotarod (Fig.…”

Innovative Therapeutic Approaches for Improving Patient Life Condition with a Neurological Lysosomal Disease

“…The observation that the increase of these mediators was accompanied by progressive microglial activation and expansion supports the hypothesis that inflammation is the major cause of neurodegeneration in gangliosidoses. This microglial activation is a characteristic shared by numerous neurodegenerative diseases (Minagar et al, 2002) and other lysosomal diseases, such as MPS I, MPS IIIB (Ohmi et al, 2003), Niemann-Pick type C (German et al, 2002), Krabbe disease (Wu et al, 2000), MPS VII (Richard et al, 2008) and MPS IIIA (Arfi et al, 2011).…”

“…Inflammation is known to be implicated in numerous neurodegenerative diseases, and has been recently well characterized in murine models of GM1/GM2 gangliosidoses (Myerowitz et al, 2002, Jeyakumar et al, 2003, as well as in mouse models of Metachromatic Leukodystrophy (Hess et al, 1996), Niemann-Pick C disease (German et al, 2002), MPS I (Ohmi et al, 2003), MPS IIIB (Ohmi et al, 2003;Villani et al, 2007) and MPS IIIA (Fraldi et al, 2007). Moreover, our previous study on a mouse model of MPS VII showed an extensive upregulation of genes related to an inflammatory process dominated by activated microglia, astrogliosis and celldeath, suggesting that inflammation might participate in neurodegeneration (Richard et al, 2008).…”