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Human pluripotent stem cell?derived A10 dopaminergic neurons specifically integrate into host circuits and relieve depression

ABSTRACT: Ventral Tegmental Area (VTA) dopaminergic neuron group (A10) one of the important subtype of midbrain dopaminergic (mDA) neurons plays a crucial role in regulation of mainly brain functions and has been related into various psychiatric disorders. Despite the great achievements in generation of mDA neurons from pluripotent stem cells, the subtype-specific mDA differentiation especially A10 group still remains challenging. Here, we report an efficient differentiation paradigm for hPSCs to generate specific A10 subtype mDA neurons. The differentiation paradigm revealed that post-mitotic patterning by NOTCH inhibitor, GDNF and AA induced the specification of A10 subtype. The hPSC-derived neurons exhibited characteristic of A10 subtype from molecular expression, electrophysiological properties and neural innervation. Considering the dysfunction of A10 mDA neurons has been implicated in depression, we detected that specific activation of the grafted-A10-like-mDA-neurons induced anxiolytic and antidepressant-like phenotypes on the transplanted mice. Our approach provides deep insights into the subtype specification of mDA neurons and offers a promising clinical application of these derived cells in cell transplantation therapy for disorders related to A10 mDA neurons.

ORGANISM(S): Homo sapiens

PROVIDER: GSE213212 | GEO | 2026/02/23

REPOSITORIES: GEO

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Project description:Mutations in the SNCA gene cause autosomal dominant Parkinson’s disease (PD), with progressive loss of dopaminergic neurons in the substantia nigra, and accumulation of aggregates of α-synuclein. However, the sequence of molecular events that proceed from the SNCA mutation during development, to its end stage pathology is unknown. Utilising human induced pluripotent stem cells (hiPSCs) with SNCA mutations, we resolved the temporal sequence of pathophysiological events that occur during neuronal differentiation in order to discover the early, and likely causative, events in synucleinopathies. We adapted a small molecule-based protocol that generates highly enriched midbrain dopaminergic (mDA) neurons (>80%). We characterised their molecular identity using single-cell RNA sequencing and their functional identity through the synthesis and secretion of dopamine, the ability to generate action potentials, and form functional synapses and networks. RNA velocity analyses confirmed the developmental transcriptomic trajectory of midbrain neural precursors into different mDA neuronal clusters. To characterise the synucleinopathy, we adopted super-resolution methods to determine the number, size, and structure of aggregates in SNCA-mutant mDA neurons. By day 27 of differentiation, prior to maturation to mDA neurons of molecular and functional identity, we demonstrate the formation of small aggregates; specifically, β-sheet rich oligomeric aggregates, in SNCA-mutant midbrain immature neurons. The aggregation progresses over time to accumulate phosphorylated and fibrillar aggregates. When the midbrain neurons were functional, we observed impaired intracellular calcium signalling, evidenced with an increased basal calcium level and impairments in both cytosolic and mitochondrial calcium rearrangements. Once midbrain identity fully developed, SNCA-mutant neurons exhibited mitochondrial dysfunction, oxidative stress, lysosomal swelling as well as an upregulation of mitophagy and autophagy. In addition, SNCA-mutant neurons displayed pathophysiological excitability, revealed as a depolarised resting membrane potential, an increased input resistance, and impaired firing properties. Ultimately these multiple cellular stresses lead to an increase in cell death by day 62 post-differentiation. Our differentiation paradigm generates an efficient model for studying disease mechanisms in PD, and highlights that protein misfolding to generate intraneuronal oligomers is one of the earliest critical events driving disease in human neurons, rather than a late-stage hallmark of the disease.

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Human pluripotent stem cell?derived A10 dopaminergic neurons specifically integrate into host circuits and relieve depression

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