Abstract
Mucopolysaccharidosis (MPS) IIIB is a devastating neuropathic lysosomal storage disease with complex pathology. This study identifies molecular signatures in peripheral blood that may be relevant to MPS IIIB pathogenesis using a mouse model. Genome-wide gene expression microarrays on pooled RNAs showed dysregulation of 2,802 transcripts in blood from MPS IIIB mice, reflecting pathological complexity of MPS IIIB, encompassing virtually all previously reported and as yet unexplored disease aspects. Importantly, many of the dysregulated genes are reported to be tissue-specific. Further analyses of multiple genes linked to major pathways of neurodegeneration demonstrated a strong brain-blood correlation in amyloidosis and synucleinopathy in MPS IIIB. We also detected prion protein (Prnp) deposition in the CNS and Prnp dysregulation in the blood in MPS IIIB mice, suggesting the involvement of Prnp aggregation in neuropathology. Systemic delivery of trans-BBB-neurotropic rAAV9-hNAGLU vector mediated not only efficient restoration of functional α-N-acetylglucosaminidase and clearance of lysosomal storage pathology in the central nervous system (CNS) and periphery, but also the correction of impaired neurodegenerative molecular pathways in the brain and blood. Our data suggest that molecular changes in blood may reflect pathological status in the CNS and provide a useful tool for identifying potential CNS-specific biomarkers for MPS IIIB and possibly other neurological diseases.
Highlights
Mucopolysaccharidosis (MPS) IIIB (OMIM #: 252920), is an autosomal recessive disorder caused by mutations in the gene that encodes a-N-acetylglucosaminidase (NAGLU), a lysosomal acid hydrolase that is essential in the stepwise degradation of heparan sulfate (HS) glycosaminoglycans (GAG) [1]
While qRT-PCR showed no significant change in App at the mRNA level in the brain (Fig. 2a), using ELISA, we detected a significant increase in phosphorylated App, the suspected pathogenic form, in the cortical brain tissues of 6 mo-old MPS IIIB mice (Fig. 2d)
Using ELISA, we detected a marked reduction of phosphorylated App (pApp) in the cortex (Fig. 2d) of mice receiving Recombinant AAV9 (rAAV9)-hNAGLU vector. These results demonstrate that restoration of NAGLU activity in the central nervous system (CNS) led to the correction of neurodegeneration in MPS IIIB mice, which correlated with normalization of ostensibly CNS-specific transcripts in blood
Summary
Mucopolysaccharidosis (MPS) IIIB (OMIM #: 252920), is an autosomal recessive disorder caused by mutations in the gene that encodes a-N-acetylglucosaminidase (NAGLU), a lysosomal acid hydrolase that is essential in the stepwise degradation of heparan sulfate (HS) glycosaminoglycans (GAG) [1]. The resulting enzyme deficiency leads to a buildup of HS-GAGs within the lysosomes. The disease causing alleles of MPS IIIB are highly polymorphic, with over 80 mutations identified [2]. The lysosomal accumulation of HS-GAGs results in clinical disease, presenting predominantly severe progressive neurological disorders. Somatic manifestations of MPS IIIB do occur in all patients, but are mild, relative to other forms of MPS. Infants appear normal at birth but develop profound neurological manifestation at the age of 3–4 years, including reduced cognitive capacity, hyperactivity, seizures, and death [2]
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