Neuropathology in Mouse Models of Mucopolysaccharidosis Type I, IIIA and IIIB

Abstract

Mucopolysaccharide diseases (MPS) are caused by deficiency of glycosaminoglycan (GAG) degrading enzymes, leading to GAG accumulation. Neurodegenerative MPS diseases exhibit cognitive decline, behavioural problems and shortened lifespan. We have characterised neuropathological changes in mouse models of MPSI, IIIA and IIIB to provide a better understanding of these events.Wild-type (WT), MPSI, IIIA and IIIB mouse brains were analysed at 4 and 9 months of age. Quantitative immunohistochemistry showed significantly increased lysosomal compartment, GM2 ganglioside storage, neuroinflammation, decreased and mislocalised synaptic vesicle associated membrane protein, (VAMP2), and decreased post-synaptic protein, Homer-1, in layers II/III-VI of the primary motor, somatosensory and parietal cortex. Total heparan sulphate (HS), was significantly elevated, and abnormally N-, 6-O and 2-O sulphated compared to WT, potentially altering HS-dependent cellular functions. Neuroinflammation was confirmed by significantly increased MCP-1, MIP-1α, IL-1α, using cytometric bead arrays. An overall genotype effect was seen in all parameters tested except for synaptophysin staining, neuronal cell number and cortical thickness which were not significantly different from WT. MPSIIIA and IIIB showed significantly more pronounced pathology than MPSI in lysosomal storage, astrocytosis, microgliosis and the percentage of 2-O sulphation of HS. We also observed significant time progression of all genotypes from 4–9 months in lysosomal storage, astrocytosis, microgliosis and synaptic disorganisation but not GM2 gangliosidosis. Individual genotype*time differences were disparate, with significant progression from 4 to 9 months only seen for MPSIIIB with lysosomal storage, MPSI with astrocytocis and MPSIIIA with microgliosis as well as neuronal loss. Transmission electron microscopy of MPS brains revealed dystrophic axons, axonal storage, and extensive lipid and lysosomal storage. These data lend novel insight to MPS neuropathology, suggesting that MPSIIIA and IIIB have more pronounced neuropathology than MPSI, yet all are still progressive, at least in some aspects of neuropathology, from 4–9 months.

Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy

“…Secondary to the lysosomal pathology in neurons and glial cells, the brains of MPS IIIA mice are characterized by the presence of extensive neuroinflammation (8,20), a common feature of MPS III in humans (34,35). To evaluate the effect of AAV9-Sgsh gene transfer on brain inflammation, MPS IIIA mice injected with AAV9-Sgsh or AAV9-null vector were analyzed in parallel to WT mice 4 months after vector delivery.…”

“…There is no cure for MSP IIIA. A mouse model of the disease derived from a spontaneous mutation in the catalytic domain of sulfamidase (5) exists and closely resembles the human disease in terms of neurodegeneration, neuroinflammation, hepatosplenomegaly, and shortened lifespan (6)(7)(8).…”

Near-Complete Correction of Profound Metabolomic Impairments Corresponding to Functional Benefit in MPS IIIB Mice after IV rAAV9-hNAGLU Gene Delivery

“…1,3 While detailed mechanisms of pathology, especially the neuropathology of MPS III, are not yet well understood, numerous studies have reported cascades of complex secondary pathological events in the CNS, including broad metabolic impairments, [4][5][6] neuroinflammation, 5,7-11 oxidative stress, 10,12 autophagy, 13,14 and neurodegeneration. 7,9,11,[15][16][17][18][19][20] It is worth noting that many of these secondary neuropathological features of MPS IIIB, such as b-amyloid (Ab) aggregation, 15,18 tauopathy, 17,18 synucleinopathy, 16,19 oxidative stress, 10,12 and neuroimflammation, 5,[7][8][9][10][11] are also common hallmarks of other neurodegenerative diseases like Alzheimer's (AD) 21,22 and Parkinson's disease (PD). 23,24 In addition, our recent studies demonstrate widespread profound neuropathology in the peripheral nervous system (PNS), 25 indicating that neuropathological manifestation affects the entire nervous system.…”

Ganglioside accumulation in activated glia in the developing brain: comparison between WT and GalNAcT KO mice

“…It has been shown that while GM2 is normally a minor ganglioside in the nervous system, it is transiently elevated during a restricted period of brain development ( 22 ) and signifi cantly elevated not only in the brain of GM2 gangliosidosis, but also in the brain of other lysosomal storage disorders such as Niemann-Pick C disease, mucolipidosis IV, and mucopolysaccharidoses (23)(24)(25)(26)(27)(28)(29)(30). In addition, accumulation of GM2 has been observed in neurodegenerative diseases such as Alzheimer disease (31)(32)(33) and Angelmanlike syndrome ( 34 ), and in rodent acute brain injury models such as blast-induced mild traumatic brain injury ( 35 ) and a transient focal cerebral ischemia model ( 36 ).…”