Abstract
Homozygous mutations in the glucocerebrosidase (GBA) gene result in Gaucher disease (GD), the most common lysosomal storage disease. Recent genetic studies have revealed that GBA mutations confer a strong risk for sporadic Parkinson’s disease (PD). To investigate how GBA mutations cause PD, we generated GBA nonsense mutant (GBA-/-) medaka that are completely deficient in glucocerebrosidase (GCase) activity. In contrast to the perinatal death in humans and mice lacking GCase activity, GBA-/- medaka survived for months, enabling analysis of the pathological progression. GBA-/- medaka displayed the pathological phenotypes resembling human neuronopathic GD including infiltration of Gaucher cell-like cells into the brains, progressive neuronal loss, and microgliosis. Detailed pathological findings represented lysosomal abnormalities in neurons and alpha-synuclein (α-syn) accumulation in axonal swellings containing autophagosomes. Unexpectedly, disruption of α-syn did not improve the life span, formation of axonal swellings, neuronal loss, or neuroinflammation in GBA-/- medaka. Taken together, the present study revealed GBA-/- medaka as a novel neuronopathic GD model, the pahological mechanisms of α-syn accumulation caused by GCase deficiency, and the minimal contribution of α-syn to the pathogenesis of neuronopathic GD.
Highlights
Gaucher disease (GD) is the most common lysosomal storage disease and is caused by homozygous mutations in glucocerebrosidase (GBA)
Recent genetic studies have revealed that mutations in glucocerebrosidase (GBA), a causative gene of Gaucher disease (GD), are a strong risk for Parkinson’s disease (PD)
Its pathological mechanisms leading to PD remain largely unknown
Summary
Gaucher disease (GD) is the most common lysosomal storage disease and is caused by homozygous mutations in glucocerebrosidase (GBA). Mutations in GBA lead to decreased enzymatic activity of glucocerebrosidase (GCase) and result in the accumulation of its substrates, glucocerebroside and glucosylsphingosine[1,2]. The accumulation of lipid-laden macrophages, called Gaucher cells, are observed in the affected organs. Neurological manifestations of neuronopathic forms include brainstem dysfunction, intellectual disability, seizures, and myoclonic movement. Pathological features of neuronopathic forms are neuronal loss, astrogliosis, microgliosis, and perivascular accumulation of Gaucher cells[3]. The most severe neuronopathic form, called the perinatal lethal type, has been reported[4]. Common presentations of patients with the perinatal lethal type are hydrops fetalis and congenital ichthyosis. Because currently available therapies are ineffective for neurological manifestations, a strong demand exists for elucidation of the pathological mechanisms and the development of novel therapies
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