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A human striatal-midbrain assembloid model of alpha-synuclein propagation.
Animal models of the pathology of Parkinson's disease (PD) have provided most of the treatments to date, but the disease is restricted to human patients. In vitro models using human pluripotent stem cell (hPSC)-derived neural organoids have provided improved access to study PD aetiology. This study established a method to generate human striatal-midbrain assembloids (hSMAs) from hPSCs for modelling alpha-synuclein (α-syn) propagation and recapitulating basal ganglia circuits, including nigrostriatal and striatonigral pathways. Human striatal organoids and midbrain organoids were generated using a stepwise differentiation protocol from hPSCs, and both regionalized neural organoids were assembled to form hSMAs, mimicking some basal ganglia circuits. Both the nigrostriatal and striatonigral pathways were present, and the neurons, such as dopaminergic neurons and GABAergic neurons, were electrophysiologically active in the hSMAs. Development of hSMAs in the presence of increased α-syn from SNCA overexpression induced nigrostriatal system damage, which is typical of the disease. Using the α-syn-linker-mKO2 reporter and a bimolecular fluorescence complementation system, we demonstrated that fluorescent α-syn was retrogradely transported from the striatal area to dopaminergic neurons of the midbrain area and exhibited α-syn aggregates and Lewy body-like inclusions. Furthermore, phosphorylated and detergent-resistant α-syn aggregates, similar to the pathological form in human patients, accumulated in the midbrain area of hSMAs. Treatment with a protein aggregation inhibitor (Anle138b) and an autophagy inducer (rapamycin) reduced α-syn aggregation, indicating the potential of hSMAs for drug testing. This study established hSMAs as a novel platform for modelling PD, demonstrating α-syn propagation and associated neural pathologies. These assembloids offer significant potential for developing therapeutic strategies and understanding the mechanisms of PD progression.
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Network and Microcircuitry Development in Human Brain Organoids.
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Patient-specific midbrain organoids with CRISPR correction recapitulate neuronopathic Gaucher disease phenotypes and enable evaluation of novel therapies.
Neuronopathic Gaucher disease (nGD) is a lysosomal storage disorder caused by GBA1 mutations, leading to defective acid β-glucosidase (GCase) and accumulation of glycosphingolipid substrates, causing inflammation and neurodegeneration. Patients with nGD manifest severe neurological symptoms, but current animal models fail to fully recapitulate the human condition, posing a major barrier to the development of effective therapies targeting the brain. To bridge this gap, we have developed midbrain-like organoids (MLOs) from human induced pluripotent stem cells of nGD patients with GBA1L444P/P415R and GBA1L444P/RecNcil mutations to model nGD brain pathogenesis. These nGD MLOs exhibited GCase deficiency, resulting in diminished enzymatic function, accumulation of lipid substrates, widespread transcriptomic changes, and impaired dopaminergic neuron differentiation, mirroring nGD pathology. GBA1 mutation correction mediated by CRISPR/Cas9 restored GCase activity, normalized lipid substrate levels, and rescued dopaminergic neuron function, confirming the causal role of GBA1 mutations during early brain development. Using this novel platform, we further evaluated therapeutic strategies, including SapC-DOPS nanovesicles delivering GCase, AAV9-GBA1 gene therapy, and substrate reduction therapy with GZ452, a glucosylceramide synthase inhibitor currently under clinical investigation. These treatments either restored GCase activity, reduced lipid substrate accumulation, improved autophagic and lysosomal abnormalities, or ameliorated dysregulated genes involved in neural development. These patient-specific, 3D neural models offer a transformative, physiologically relevant platform for unraveling disease mechanisms and accelerating the discovery of therapies for patients with nGD.
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Androgen signal for brain size.
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Microglia regulate GABAergic neurogenesis in prenatal human brain through IGF1.
GABAergic neurons are essential cellular components of neural circuits. Their abundance and diversity have increased significantly in the human brain, contributing to the expanded cognitive capacity of humans1. However, the developmental mechanism underlying the extended production of GABAergic neurons in the human brain remains elusive. Here we uncovered the microglial regulation of the sustained proliferation of GABAergic progenitors and neuroblasts in the human medial ganglionic eminence (hMGE). We showed that microglia are preferentially distributed in the proliferating zone and identified insulin-like growth factor 1 (IGF1) and its receptor IGR1R as the predicted top ligand-receptor pair underlying microglia-progenitor communication in the prenatal hMGE. Using our newly developed neuroimmune hMGE organoids, which mimic the hMGE cytoarchitecture and developmental trajectory, we demonstrated that microglia-derived IGF1 promotes progenitor proliferation and production of GABAergic neurons. Conversely, IGF1-neutralizing antibodies and IGF1 knockout human embryonic stem-cell-induced microglia abolish the induced microglia-mediated progenitor proliferation. Together, these findings revealed a previously unappreciated role of microglia-derived IGF1 in promoting the proliferation of neural progenitors and the development of GABAergic neurons in the human brain.
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Fine structures of the teleostean vagal lobe.
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Fixation of the central nervous system by perfusion with aldehydes and its effect on the extracellular space as seen by electron microscopy.
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[Ultrastructural basis of trophic interactions in the central nervous system].
Cytological aspects of metabolic processes between capillaries and nerve cells, as well as between different elements of neurons were studied electron microscopically. The sensomotor cortex, hippocampus, anterior tubercles of corpora quadrigemina, geniculate body were studied in rats, adult cats and 4-day-old kittens. Metabolic ultrastructure was demonstrated by means of vesicles formed by micropinocytosis, in the endothelial wall of the capillary, in the synaptic plaques, in the growth cones. Coincidence of pinocytic processes with active synaptic zones, especially in the developing nervous system, was revealed. The phenomena of intraneuronal metabolism by means of cytoplasmic fragments (clasmatosis) in the area of synapses were described. Endogenic (formed in the zone of the lamellar apparatus) and exogenic (pinocytic) trophic vesicles were compared. In young animals the exchange of the trophic vesicles was demonstrated to precede the synaptic transmission, while in adult animals it seemed to supplement a short-lasting synaptic interconnection.
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The morphologic similarities of human and canine globoid leukodystrophy. Thin section and freeze-fracture studies.
Human and canine globoid leukodystrophy are shown to be indistinguishable morphologically. Both have characteristic deposits with polygonal cross-sectional profiles in addition to twisted ribbon-like structures. The specificity of the deposits is emphasized, and their laminated nature is corroborated by the freeze-fracture studies. Their apparently hollow profiles in cross section are thought to be produced by the tight arrangement of the bilayers that prevent penetration of the stain.
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m6A deficiency impairs hypothalamic neurogenesis of feeding-related neurons in mice and human organoids and leads to adult obesity in mice.
N6-methyladenosine (m6A), the most prevalent internal modification on mRNAs, plays important roles in the nervous system. Whether neurogenesis in the hypothalamus, a region critical for controlling appetite, is regulated by m6A signaling, especially in humans, remains unclear. Here, we showed that deletion of m6A writer Mettl14 in the mouse embryonic hypothalamus led to adult obesity, with impaired glucose-insulin homeostasis and increased energy intake. Mechanistically, deletion of Mettl14 leads to hypothalamic arcuate nucleus neurogenesis deficits with reduced generation of feeding-related neurons and dysregulation of neurogenesis-related m6A-tagged transcripts. Deletion of m6A writer Mettl3 or m6A reader Ythdc1 shared similar phenotypes. METTL14 or YTHDC1 knockdown also led to reduced generation of feeding-related neurons in human brain subregion-specific arcuate nucleus organoids. Our studies reveal a conserved role of m6A signaling in arcuate nucleus neurogenesis in mice and human organoids and shed light on the developmental basis of epitranscriptomic regulation of food intake and energy homeostasis.