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. 2016 Jun 2;12(6):1059-60.
doi: 10.1080/15548627.2015.1046671. Epub 2015 May 22.

Lysosomal storage of heparan sulfate causes mitochondrial defects, altered autophagy, and neuronal death in the mouse model of mucopolysaccharidosis III type C

Alexey V Pshezhetsky  1
Affiliations

Lysosomal storage of heparan sulfate causes mitochondrial defects, altered autophagy, and neuronal death in the mouse model of mucopolysaccharidosis III type C

Alexey V Pshezhetsky. Autophagy. .

Abstract

The genetic metabolic disease mucopolysaccharidosis III type C (MPS IIIC, Sanfilippo disease type C) causes progressive neurodegeneration in infants and children, leading to dementia and death before adulthood. MPS IIIC stands out among lysosomal diseases because it is the only one caused by a deficiency not of a hydrolase but of HGSNAT (heparan--glucosaminide N-acetyltransferase), which catalyzes acetylation of glycosaminoglycan heparan sulfate (HS) prior to its hydrolysis.

Keywords: acetyl-CoA; glycosaminoglycans; heparan sulfate; knockout mouse model; lysosome; mucopolysaccharidosis; α-glucosaminide N-acetyltransferase.

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Figures

Figure 1.
Figure 1.
Pathological changes in the brains of Hgsnat-Geo mice. (A) Accumulation of PAS-positive granular material in neurons in the brain of a Hgsnat-Geo mouse. Microglia show the presence of storage, and have a foam-like appearance. Somatosensory cortex (layer V) of 12-mo-old Hgsnat-Geo and WT mice. Bars: 50 µm; bars in the inserts: 30 µm. (B) Accumulation of granular autofluorescent materials in neurons of somatosensory cortex (layer V) of 12-mo-old Hgsnat-Geo and WT mice. Bars: 100 µm; bar in the insert: 30 µm. (C) Storage pattern in microglia (asterisk): massive accumulation of vacuoles with single limiting membranes and a sparse fine content in the cytoplasm. Bar: 2 µm. (D) Lysosomal system in a cortical neuron is expanded and massively overloaded by electron dense material (marked by arrows). Bar: 2 µm. (E) Increased LC3-II levels in the brain tissues of Hgsnat-Geo (H-G) mice at 6 and 10 mo. Inset graph shows ratios (means and SD) of signal intensities for LC3-II and LC3-I. * P < 0.05 in unpaired 2-tailed t test. (F) At 12 mo mitochondria in neurons of Hgsnat-Geo mice are displaying swelling and disorganization of their inner membranes (marked by arrowheads and asterisks). Bar: 1 µm. (G) Mitochondrial population in neurons of WT mice at 12 mo is relatively uniform and is composed of normally shaped mitochondria. Bar: 1 µm. Reproduced from Martins et al. Brain. 2015; 138:336–55, with permission of the publisher.
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