Abstract
Mucopolysaccharidoses (MPS) are the group of lysosomal storage disorders caused by deficiencies of enzymes involved in the stepwise degradation of glycosaminoglycans. To identify brain pathology common for neurological MPS, we conducted a comprehensive analysis of brain cortex tissues from post-mortem autopsy materials of eight patients affected with MPS I, II, IIIA, IIIC, and IIID, and age-matched controls. Frozen brain tissues were analyzed for the abundance of glycosaminoglycans (heparan, dermatan, and keratan sulfates) by LC-MS/MS, glycosphingolipids by normal phase HPLC, and presence of inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor superfamily member 10 (TNFSF10) by Western blotting. Fixed tissues were stained for the markers for microgliosis, astrogliosis, misfolded proteins, impaired autophagy, and GM2 ganglioside. Our results demonstrate that increase of heparan sulfate, decrease of keratan sulfate, and storage of simple monosialogangliosides 2 and 3 (GM2 and GM3) as well as the neutral glycosphingolipid, LacCer, together with neuroinflammation and neuronal accumulation of misfolded proteins are the hallmarks of brain pathology in MPS patients. These biomarkers are similar to those reported in the corresponding mouse models, suggesting that the pathological mechanism is common for all neurological MPS in humans and mice.
Highlights
More than 30% of patients affected with lysosomal diseases have mucopolysaccharidoses (MPS), disorders affecting the enzymes involved in the stepwise degradation of glycosaminoglycans (GAGs) [1,2,3,4]
Our results demonstrate that an increase of heparan sulfate (HS) (HS/dermatan sulfate (DS)), a decrease of keratan sulfate (KS), secondary lipidome changes, neuroinflammation, and protein folding defects are the most striking features of central nervous system (CNS) pathology in MPS patients with neurological forms
Frozen and/or paraformaldehyde (PFA)-fixed somatosensory cortex tissues from eight MPS patients and seven non-MPS, controls matched for age and sex, collected at post-mortem autopsy were obtained from National Institutes of Health (NIH) NeuroBioBank
Summary
More than 30% of patients affected with lysosomal diseases have mucopolysaccharidoses (MPS), disorders affecting the enzymes involved in the stepwise degradation of glycosaminoglycans (GAGs) [1,2,3,4]. This mechanism involves general inflammation reactions, release of multifunctional cytokines and oxidative stress, pathological changes in the mitochondrial system and vesicular transport, progressive accumulation of lipid and protein aggregates, and closely resembles pathological cascades in age-related neurodegenerative tauopathies [9,10,11,12] While these studies provide crucial information essential for our understanding of the diseases, it is important to understand that the majority have been conducted using the animal (mainly mouse) models of the disease, sometimes demonstrating clinical phenotypes different from those of the human patients. Our results demonstrate that an increase of HS (HS/DS), a decrease of KS, secondary lipidome changes, neuroinflammation, and protein folding defects are the most striking features of CNS pathology in MPS patients with neurological forms
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