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.
Highlights
Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder with a broad spectrum of severities
Two therapeutic approaches are approved for the visceral manifestations of GD, i.e. enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) [9, 10]
We demonstrated that 9V/null mice had progressive accumulation of substrates in the brain, predisposing to brain pathology including αSyn and p-Tau accumulation
Summary
Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder with a broad spectrum of severities. In GD, mutations of GBA1 lead to defective function of acid β-glucosidase (GCase) and subsequent accumulation of its substrates, glucosylceramide (GC) and glucosylsphingosine (GS) [1]. Accumulation of these substrates affects normal cell function and promotes disease progression in the viscera and central nervous systems (CNS) [1,2,3,4]. GD type 3 patients present various signs of neuronopathic and visceral involvement with chronic progression, and may survive into the 2nd to the 5th decades of life [1, 4]. There have been no effective treatment options for the neurological sequelae of GD patients and innovative therapies are still needed
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
