Characterization of Fluid Biomarkers Reveals Lysosome Dysfunction and Neurodegeneration in Neuronopathic MPS II Patients.

Abstract

Mucopolysaccharidosis type II is a lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS) and characterized by the accumulation of the primary storage substrate, glycosaminoglycans (GAGs). Understanding central nervous system (CNS) pathophysiology in neuronopathic MPS II (nMPS II) has been hindered by the lack of CNS biomarkers. Characterization of fluid biomarkers has been largely focused on evaluating GAGs in cerebrospinal fluid (CSF) and the periphery; however, GAG levels alone do not accurately reflect the broad cellular dysfunction in the brains of MPS II patients. We utilized a preclinical mouse model of MPS II, treated with a brain penetrant form of IDS (ETV:IDS) to establish the relationship between markers of primary storage and downstream pathway biomarkers in the brain and CSF. We extended the characterization of pathway and neurodegeneration biomarkers to nMPS II patient samples. In addition to the accumulation of CSF GAGs, nMPS II patients show elevated levels of lysosomal lipids, neurofilament light chain, and other biomarkers of neuronal damage and degeneration. Furthermore, we find that these biomarkers of downstream pathology are tightly correlated with heparan sulfate. Exploration of the responsiveness of not only CSF GAGs but also pathway and disease-relevant biomarkers during drug development will be crucial for monitoring disease progression, and the development of effective therapies for nMPS II.

• Authors: Akhil Bhalla, Ritesh Ravi, Meng Fang, Annie Arguello, Sonnet S Davis, Chi-Lu Chiu, Jessica R Blumenfeld, Hoang N Nguyen, Timothy K Earr, Junhua Wang, Giuseppe Astarita, Yuda Zhu, Damian Fiore, Kimberly Scearce-Levie, Dolores Diaz, Heather Cahan, Matthew D Troyer, Jeffrey M Harris, Maria L Escolar
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 15 (Jul 22 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 32707880 (Publication Type: Journal Article)

Chemical References

• Biomarkers
• Gangliosides
• Glycosaminoglycans
• Neurofilament Proteins
• Recombinant Proteins
• neurofilament protein L
• Dermatan Sulfate
• Heparitin Sulfate
• Iduronate Sulfatase

Topics

• Adolescent
• Animals
• Biomarkers (metabolism)
• Brain (metabolism, pathology)
• Child
• Child, Preschool
• Dermatan Sulfate (blood, cerebrospinal fluid, metabolism)
• Enzyme Replacement Therapy
• Female
• Gangliosides (metabolism)
• Glycosaminoglycans (cerebrospinal fluid, metabolism)
• Hematopoietic Stem Cell Transplantation
• Heparitin Sulfate (blood, cerebrospinal fluid, metabolism)
• Humans
• Iduronate Sulfatase (genetics, metabolism, pharmacology)
• Infant
• Inflammation (metabolism)
• Lipid Metabolism
• Lysosomes (metabolism, pathology)
• Male
• Mass Spectrometry
• Mice
• Mice, Knockout
• Mucopolysaccharidosis II (blood, cerebrospinal fluid, metabolism, therapy)
• Neurofilament Proteins (metabolism)
• Recombinant Proteins (genetics, metabolism)