Central nervous system inflammation is a hallmark of pathogenesis in mouse models of GM1 and GM2 gangliosidosis

Abstract

Mouse models of the GM2 gangliosidoses [Tay-Sachs, late onset Tay-Sachs (LOTS), Sandhoff] and GM1 gangliosidosis have been studied to determine whether there is a common neuro-inflammatory component to these disorders. During the disease course, we have: (i) examined the expression of a number of inflammatory markers in the CNS, including MHC class II, CD68, CD11b (CR3), 7/4, F4/80, nitrotyrosine, CD4 and CD8; (ii) profiled cytokine production [tumour necrosis factor alpha (TNF alpha), transforming growth factor (TGF beta 1) and interleukin 1 beta (IL1 beta)]; and (iii) studied blood-brain barrier (BBB) integrity. The kinetics of apoptosis and the expression of Fas and TNF-R1 were also assessed. In all symptomatic mouse models, a progressive increase in local microglial activation/expansion and infiltration of inflammatory cells was noted. Altered BBB permeability was evident in Sandhoff and GM1 mice, but absent in LOTS mice. Progressive CNS inflammation coincided with the onset of clinical signs in these mouse models. Substrate reduction therapy in the Sandhoff mouse model slowed the rate of accumulation of glycosphingolipids in the CNS, thus delaying the onset of the inflammatory process and disease pathogenesis. These data suggest that inflammation may play an important role in the pathogenesis of the gangliosidoses.

Gangliosides as apoptotic signals in ER stress response

“…[24][25][26] The presence of reactive astrocytes is indicative of an elicited neuroinflammatory response, and the biochemical heterogeneity and adaptive plasticity may reflect differences in microenvironmental cues, such as the combination of cytokines, growth factors, adhesion molecules, and other signals emanating from injured neurons, activated microglia, endothelial cells, and vascular components. [27][28][29] As mentioned in the Introduction, the amount and composition of gangliosides in a cell is species-and cell type-specific. In the central nervous system (CNS), gangliosides constitute 10-12% of the total lipid content, and in the mammalian brain, GM1 ganglioside is the most abundant glycolipid.…”

“…48,57 In the GM1 mouse model, this phenotype is accompanied by gradual deterioration of motor functions 48,56 and progressive CNS inflammation. 28 Owing to their similarities to the corresponding human diseases, these mouse models are a proverbial gold mine for studying molecular pathogenesis associated with altered ganglioside metabolism.…”

Early deficits in motor coordination and cognitive dysfunction in a mouse model of the neurodegenerative lysosomal storage disorder, Sandhoff disease

“…Sandhoff disease arises from defects in the gene encoding the β-subunit (hexb) of β-Nacetyl-d-hexosaminide N-acetylhexosaminohydrolase (EC 3.2.1.52) normally involved in the sequential catabolism of gangliosides and other glycoconjugates [11]. Sandhoff patients have widespread brain pathology which results in clinical symptoms including progressive mental and motor deterioration [10,11,21].Two transgenic murine models of Sandhoff disease exist [23,25] that, like the human equivalent, exhibit premature death and display widespread neuronal storage of ganglioside, in addition to gliotic and inflammatory reactions and neuronal cell death [11,16,23,25,27]. The Sandhoff models have engendered much research directed at overcoming the challenges [1,2,4,11,14,15,18,20].…”

“…The Sandhoff models have engendered much research directed at overcoming the challenges [1,2,4,11,14,15,18,20]. The knockout model [25] presented here displays ataxia, tremor, muscle wasting, and deficits in motor reflex, coordination and balance [1,4,7,8,13,14,16,18,20,22,25,27,28]. However, systematic studies examining cognitive or affective outcomes are lacking [25].…”

“…Both latency (time to cross the beam from end to end) and number of slips (each time a paw fell under the beam midline) were assessed as measures of motor coordination. In the rotarod test, latency to fall from a rotating rod (acceleration increased by 0.5 cm/s every 5 s) was scored automatically with infrared sensors in a Rotamex 5 rotarod (Columbus Inst, Ohio) with four trials per day over 2 days.Behavioral tests were primarily conducted on mice of 79(±2) days old, an age that in most previous assays showed no deficits, but were also performed on some at 66(± 2) and 97(± 2) days when had been typically reported as normal or displaying deficits, respectively [1,4,7,8,13,14,16,18,20,22,25,27,28]. All data are shown as mean ± S.E.M.…”