Combination of acid β-glucosidase mutation and Saposin C deficiency in mice reveals Gba1 mutation dependent and tissue-specific disease phenotype

Abstract

Gaucher disease is caused by mutations in GBA1 encoding acid β-glucosidase (GCase). Saposin C enhances GCase activity and protects GCase from intracellular proteolysis. Structure simulations indicated that the mutant GCases, N370S (0 S), V394L (4L) and D409V(9V)/H(9H), had altered function. To investigate the in vivo function of Gba1 mutants, mouse models were generated by backcrossing the above homozygous mutant GCase mice into Saposin C deficient (C*) mice. Without saposin C, the mutant GCase activities in the resultant mouse tissues were reduced by ~50% compared with those in the presence of Saposin C. In contrast to 9H and 4L mice that have normal histology and life span, the 9H;C* and 4L;C* mice had shorter life spans. 9H;C* mice developed significant visceral glucosylceramide (GC) and glucosylsphingosine (GS) accumulation (GC»GS) and storage macrophages, but lesser GC in the brain, compared to 4L;C* mice that presents with a severe neuronopathic phenotype and accumulated GC and GS primarily in the brain. Unlike 9V mice that developed normally for over a year, 9V;C* pups had a lethal skin defect as did 0S;C* mice resembled that of 0S mice. These variant Gaucher disease mouse models presented a mutation specific phenotype and underscored the in vivo role of Saposin C in the modulation of Gaucher disease.

Ocular phenotypes in a mouse model of impaired glucocerebrosidase activity

“…This decrease was detected at 3 months of age and did not progress further in 17 months old mice. These data confirm GCase activity impairment in Gba KI mice in line with published reports 19 , 36 .

Figure 1 Decreased GCase activity and increased GluSph and GluCer levels in Gba KI mice.

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Sphingolipid lysosomal storage diseases: from bench to bedside

“…GCase normally works in coordination with SapC and lysosomal BMP to hydrolyze GlcCer into glucose and Cer. Therefore, in rare circumstances, GD can also be caused by a deficiency in SapC [ 65 , 111 ]. The reduced cellular capacity to degrade GSL leads to the primary accumulation of GlcCer in cells, particularly phagocytizing macrophages mainly found in the liver, spleen, and bone marrow.…”

The Role of Cholesterol in α‐Synuclein and Lewy Body Pathology in GBA1 Parkinson's Disease

“…58 Moreover, α-Syn overexpression appears to affect GA tubulation through Rab and SNARE proteins; this mechanism is involved in the GA fragmentation that occurs in PD and GBA1-PD. 58,59,63,145 Because cholesterol could ultimately control endolysosomal membrane organization, its storage could modulate GCase activity by disrupting the contact between GCase and its coactivator SapC 146,147 (Fig. 1).…”

“…It was proposed that subtle, prolonged glycolipid anomalies generate neurodegeneration at advance ages. 147,199…”

“…Glycolipid buildup is more variable and lower than observed in GD. It was proposed that subtle, prolonged glycolipid anomalies generate neurodegeneration at advance ages 147,199 …”