The importance of iPS-derived astrocytes in in the pathophysiology of GBA1-associated Parkinson disease

Authors

• A Eghbali
• B Stubblefield
• E Sidransky
• E Aflaki

Abstract

Astrocytes, though not studied well, provide critical support for neuronal function by providing antioxidant protection, clearing glutamate, developing and/or maintaining the blood-brain barrier, and releasing gliotransmitters and cytokines. Mutations in GBA1, the gene encoding glucocerebrosidase (GCase), which is mutated in the lysosomal disorder Gaucher disease (GD), are the most common genetic risk factor for PD. We generated astrocytes from iPSCs derived from fibroblasts of eight patients. Six fibroblasts from patients with type 1 GD (GD1), three with and three without parkinsonism (GD1-PD), including two siblings discordant for Parkinson disease and two from patients with type 2 GD. The astrocytes exhibited decreased GCase activity and stored Glucosylceramide and Glucosphingosine, when compared to a healthy control. Moreover, astrocytes from patients with GD2 and GD1 with PD had an increased in glutamate uptake and decreased in intracellular calcium in respond to ATP. Moreover, the role of monomer and aggregated α-synuclein in astrocytes neuroinflammation studied in detail. The astrocytes from patients with GD1-PD or GD2 had an increased in GFAP expression (as marker for active astrocytes) and secrete significant amount of inflammatory cytokines confirmed by proteome profiler. We studied the trafficking of α-synuclein in intravehicular bodies, and we found that astrocytes from patients with GD1-PD and GD2 accumulate αsynuclein in the late-endodome and matured cathepsin-D positive lysosomes, which also results in astrogliosis confirmed by elevation of Ki67 positive cells. αThese cells therefore represent an excellent model for exploring the potential role of astrocytes in the pathogenesis of GBA1-associated PD and neuropathic form of GD.

Scientific Focus Area: Cell Biology

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