Accelerated clinical disease and pathology in mucopolysaccharidosis type IIIB and GalNAc transferase double knockout mice

Mohammed, Eman; Snella, Elizabeth M.; Rutz-Mendicino, Michelle M.; Echevarria, Franklin D.; Awedikian, Rafi; Whitley, Elizabeth M.; Ellinwood, N. Matthew

doi:10.1016/j.ymgme.2012.07.017

Cited by 4 publications

(2 citation statements)

References 38 publications

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“…Second, storage of G M2 and G M3 gangliosides occurring in brain cerebral cortical and cerebellar neurons (McGlynn et al, 2004;Crawley et al, 2006) was previously suggested to cause neuronal apoptosis in Tay-Sachs and Sandhoff diseases where G M2 ganglioside is accumulated due to genetic defects of hexosaminidases A and B, respectively (Huang et al, 1997;Wada et al, 2000). Interestingly, recently described double-mutant MPS IIIA and IIIB mice with a knockout GalNAc transferase (Galnt3) crucial for the synthesis of gangliosides have significantly reduced lifespan and increased neurodegeneration as compared to the corresponding single-mutant MPS IIIA and MPS IIIB mice, suggesting that absence of gangliosides may also be deleterious in MPS III (Mohammed et al, 2012). Third, neurodegeneration could be caused by protein aggregates (Ginsberg et al, 1999;Hamano et al, 2008;Ohmi et al, 2009) detected in neurons of medial entorhinal cortex and the dentate gyrus and linked to impaired autophagy and/or increased extralysosomal level of heparan sulphate proteoglycans, glypicans (Ohmi et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Neuroinflammation, mitochondrial defects and neurodegeneration in mucopolysaccharidosis III type C mouse model

Martins

Hůlková

Dridi

et al. 2015

Brain

123

202

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Severe progressive neurological paediatric disease mucopolysaccharidosis III type C is caused by mutations in the HGSNAT gene leading to deficiency of acetyl-CoA: α-glucosaminide N-acetyltransferase involved in the lysosomal catabolism of heparan sulphate. To understand the pathophysiology of the disease we generated a mouse model of mucopolysaccharidosis III type C by germline inactivation of the Hgsnat gene. At 6-8 months mice showed hyperactivity, and reduced anxiety. Cognitive memory decline was detected at 10 months and at 12-13 months mice showed signs of unbalanced hesitant walk and urinary retention. Lysosomal accumulation of heparan sulphate was observed in hepatocytes, splenic sinus endothelium, cerebral microglia, liver Kupffer cells, fibroblasts and pericytes. Starting from 5 months, brain neurons showed enlarged, structurally abnormal mitochondria, impaired mitochondrial energy metabolism, and storage of densely packed autofluorescent material, gangliosides, lysozyme, phosphorylated tau, and amyloid-β. Taken together, our data demonstrate for the first time that deficiency of acetyl-CoA: α-glucosaminide N-acetyltransferase causes lysosomal accumulation of heparan sulphate in microglial cells followed by their activation and cytokine release. They also show mitochondrial dysfunction in the neurons and neuronal loss explaining why mucopolysaccharidosis III type C manifests primarily as a neurodegenerative disease.

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Section: Introductionmentioning

confidence: 99%

Neuroinflammation, mitochondrial defects and neurodegeneration in mucopolysaccharidosis III type C mouse model

Martins

Hůlková

Dridi

et al. 2015

Brain

123

202

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“…First, GAG accumulation in neurons brings about cellular changes by way of primary (intralysosomal) and secondary (extralysosomal) accumulations, which eventually give rise to gross neuroanatomical changes across various regions in the brain. Additionally, in some types of MPS, e.g., IIB, secondary accumulations of gangliosides contribute further to this process [22]. Probably in parallel, these cellular changes also generate microscopic neuropathological processes, including meganeurites in the cerebral cortex and brain stem and neuroaxonal dystrophy in the GABA (gamma-aminobutyric acid)-ergic neurons, as well as impaired autophagy.…”

Section: Neuropathological Progression In Neuropathic Mpsmentioning

confidence: 99%

Novel Enzyme Replacement Therapies for Neuropathic Mucopolysaccharidoses

Sato

Okuyama

2020

IJMS

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Although the advent of enzyme replacement therapy (ERT) for mucopolysaccharidoses (MPS) has paved the way for the treatment for these hereditary disorders, the blood brain barrier (BBB) has prevented patients with MPS involving the central nervous system (CNS) from benefitting from ERT. Therefore, finding ways to increase drug delivery into the brain across the BBB remains a crucial challenge for researchers and clinicians in the field. Attempts have been made to boost brain uptake of enzymes by targeting various receptors (e.g., insulin and transferrin), and several other administration routes have also been tested. This review summarizes the available information on clinical trials (completed, ongoing, and planned) of novel therapeutic agents with efficacy against CNS symptoms in neuropathic MPS and also discusses the common associated challenges and pitfalls, some of which may help elucidate the pathogenesis of the neurodegeneration leading to the manifold CNS symptoms. A summary of current knowledge pertaining to the neuropathological progression and resultant neuropsychiatric manifestations is also provided, because it should be useful to ERT researchers looking for better approaches to treating CNS lesions in MPS.

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