Progression of Behavioral and CNS Deficits in a Viable Murine Model of Chronic Neuronopathic Gaucher Disease

Abstract

To study the neuronal deficits in neuronopathic Gaucher Disease (nGD), the chronological behavioral profiles and the age of onset of brain abnormalities were characterized in a chronic nGD mouse model (9V/null). Progressive accumulation of glucosylceramide (GC) and glucosylsphingosine (GS) in the brain of 9V/null mice were observed at as early as 6 and 3 months of age for GC and GS, respectively. Abnormal accumulation of α-synuclein was present in the 9V/null brain as detected by immunofluorescence and Western blot analysis. In a repeated open-field test, the 9V/null mice (9 months and older) displayed significantly less environmental habituation and spent more time exploring the open-field than age-matched WT group, indicating the onset of short-term spatial memory deficits. In the marble burying test, the 9V/null group had a shorter latency to initiate burying activity at 3 months of age, whereas the latency increased significantly at ≥12 months of age; 9V/null females buried significantly more marbles to completion than the WT group, suggesting an abnormal response to the instinctive behavior and an abnormal activity in non-associative anxiety-like behavior. In the conditional fear test, only the 9V/null males exhibited a significant decrease in response to contextual fear, but both genders showed less response to auditory-cued fear compared to age- and gender-matched WT at 12 months of age. These results indicate hippocampus-related emotional memory defects. Abnormal gait emerged in 9V/null mice with wider front-paw and hind-paw widths, as well as longer stride in a gender-dependent manner with different ages of onset. Significantly higher liver- and spleen-to-body weight ratios were detected in 9V/null mice with different ages of onsets. These data provide temporal evaluation of neurobehavioral dysfunctions and brain pathology in 9V/null mice that can be used for experimental designs to evaluate novel therapies for nGD.

Value of Glucosylsphingosine (Lyso-Gb1) as a Biomarker in Gaucher Disease: A Systematic Literature Review

“…Thirty non-randomized clinical trials and observational studies with full-study reporting were assessed using the Newcastle–Ottawa scoring tool [ 3 , 26 , 33 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 ], of which 19 were deemed to have a high risk of bias (score 0–3; Table S2 ). Thirty-two animal studies were assessed using the SYRCLE risk of bias tool [ 45 , 53 , 58 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 ,…”

“…Of the 74 articles included, 56 articles pertained to lyso-Gb1 and GD pathology. They encompassed (in a non-mutually exclusive manner) ten clinical (autopsy) studies [ 54 , 55 , 56 , 57 , 58 , 59 , 61 , 62 , 63 , 93 ] and 48 studies reporting preclinical data (19 studies reporting in vitro data and 32 studies reporting in vivo data) [ 26 , 45 , 53 , 58 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 ,…”

“…Lyso-Gb1 accumulation was observed in the brain [ 53 , 65 , 67 , 68 , 69 , 70 , 72 , 73 , 76 , 82 , 83 , 84 , 85 , 86 , 88 , 89 , 90 , 91 , 111 ], viscera [ 65 , 73 , 86 , 91 ], and blood [ 111 ], but not bone, and in a wide range of neuronopathic GD murine models and one ovine model. Although murine models are highly economical, lamb brain is considered more translationally relevant to the human brain as both are gyrencephalic and have similar anatomy and physiological vital signs.…”

“…Results from 14 of 17 experimental animal models of GD have shown that lyso-Gb1 is associated with: pro-inflammatory effects [ 75 ]; hepatosplenomegaly [ 67 , 74 , 75 , 77 ]; poor hematologic [ 75 , 77 ], skeletal [ 77 ], and neurologic outcomes [ 68 , 76 , 82 , 83 ]; B-cell malignancy [ 79 ]; death [ 89 , 90 ] ( Table 3 ). Two in vivo studies did not evaluate the effect of lyso-Gb1 in specific aspects of GD pathology [ 45 , 78 ].…”

Previously unrecognized behavioral phenotype in Gaucher disease type 3

“…Mice were hyperactive, jumpy, and aggressive toward other mice and humans, biting far more often than wild-type mice or mice with other GBA1 mutations. 34 …”