Amyloidosis, synucleinopathy, and prion encephalopathy in a neuropathic lysosomal storage disease: the CNS-biomarker potential of peripheral blood.

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.

• Authors: Bartholomew J Naughton, F Jason Duncan, Darren Murrey, Tierra Ware, Aaron Meadows, Douglas M McCarty, Haiyan Fu
• Journal: PloS one (PLoS One) Vol. 8 Issue 11 Pg. e80142 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24278249 (Publication Type: Journal Article)

Chemical References

• Biomarkers
• Synucleins
• alpha-N-acetyl-D-glucosaminidase
• Acetylglucosaminidase

Topics

• Acetylglucosaminidase (genetics)
• Amyloidosis (complications)
• Animals
• Biomarkers (blood)
• Brain Diseases (complications)
• Central Nervous System (metabolism)
• Enzyme-Linked Immunosorbent Assay
• Gene Expression
• Genetic Therapy
• Humans
• Maze Learning
• Mice
• Mice, Knockout
• Mucopolysaccharidosis III (complications)
• Prion Diseases (complications)
• Real-Time Polymerase Chain Reaction
• Synucleins (metabolism)