Reactive astrocytes mediate toxicity in iPSC derived dopaminergic neurons - PubMed
6 hours ago
- #GBA Mutation
- #Reactive Astrocytes
- #Neuroinflammation
- Neuroinflammation is a hallmark of Parkinson's disease (PD), involving α-synuclein accumulation and dopaminergic neuron death.
- GBA mutations, like N370S, are a common PD risk factor, disrupting lipid metabolism, autophagy/lysosomal function, and other cellular processes.
- Using iPSC-derived midbrain astrocytes and dopaminergic neurons from control and GBA-N370S donors, along with primary mouse astrocyte cultures, the study explored astrocyte reactivity under inflammatory stimuli (TNFα and IFNγ).
- RNAseq analysis revealed severe dysregulation of calcium transport and homeostasis in reactive astrocytes, with GBA-N370S astrocytes showing increased calcium release upon cytokine treatment.
- In co-culture models, combined treatment with TNFα, IFNγ, and α-synuclein pre-formed fibrils (PFFs) led to neurotoxic effects, indicating that cytokine-activated astrocytes mediate α-synuclein PFF toxicity.
- Both control and GBA-N370S iPSC-derived midbrain astrocytes exposed to inflammatory cytokines showed reduced neurosupport, suggesting reactive astrocytes play a role in PD pathology.