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Defective proteostasis in induced pluripotent stem cell models of frontotemporal lobar degeneration.
Impaired proteostasis is associated with normal aging and is accelerated in neurodegeneration. This impairment may lead to the accumulation of protein, which can be toxic to cells and tissue. In a subset of frontotemporal lobar degeneration with tau pathology (FTLD-tau) cases, pathogenic mutations in the microtubule-associated protein tau (MAPT) gene are sufficient to cause tau accumulation and neurodegeneration. However, the pathogenic events triggered by the expression of the mutant tau protein remain poorly understood. Here, we show that molecular networks associated with lysosomal biogenesis and autophagic function are disrupted in brains from FTLD-tau patients carrying a MAPT p.R406W mutation. We then used human induced pluripotent stem cell (iPSC)-derived neurons and 3D cerebral organoids from patients carrying the MAPT p.R406W mutation and CRISPR/Cas9, corrected controls to evaluate proteostasis. MAPT p.R406W was sufficient to induce morphological and functional deficits in the lysosomal pathway in iPSC-neurons. These phenotypes were reversed upon correction of the mutant allele with CRISPR/Cas9. Treatment with mTOR inhibitors led to tau degradation specifically in MAPT p.R406W neurons. Together, our findings suggest that MAPT p.R406W is sufficient to cause impaired lysosomal function, which may contribute to disease pathogenesis and serve as a cellular phenotype for drug screening.
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Development and disease in a dish: the epigenetics of neurodevelopmental disorders.
Human neurodevelopmental disorders (NDDs) involve mutations in hundreds of individual genes, with over-representation in genes encoding proteins that alter chromatin structure to modulate gene expression. Here, we highlight efforts to model these NDDs through in vitro differentiation of patient-specific induced pluripotent stem cells into neurons. We discuss how epigenetic regulation controls normal cortical development, how mutations in several classes of epigenetic regulators contribute to NDDs, and approaches for modeling cortical development and function using both directed differentiation and formation of cerebral organoids. We explore successful applications of these models to study both syndromic and nonsyndromic NDDs and to define convergent mechanisms, addressing both the potential and challenges of using this approach to define cellular and molecular mechanisms that underlie NDDs.
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Genome-wide, integrative analysis of circular RNA dysregulation and the corresponding circular RNA-microRNA-mRNA regulatory axes in autism.
Circular RNAs (circRNAs), a class of long noncoding RNAs, are known to be enriched in mammalian neural tissues. Although a wide range of dysregulation of gene expression in autism spectrum disorder (ASD) have been reported, the role of circRNAs in ASD remains largely unknown. Here, we performed genome-wide circRNA expression profiling in postmortem brains from individuals with ASD and controls and identified 60 circRNAs and three coregulated modules that were perturbed in ASD. By integrating circRNA, microRNA, and mRNA dysregulation data derived from the same cortex samples, we identified 8170 ASD-associated circRNA-microRNA-mRNA interactions. Putative targets of the axes were enriched for ASD risk genes and genes encoding inhibitory postsynaptic density (PSD) proteins, but not for genes implicated in monogenetic forms of other brain disorders or genes encoding excitatory PSD proteins. This reflects the previous observation that ASD-derived organoids show overproduction of inhibitory neurons. We further confirmed that some ASD risk genes (NLGN1, STAG1, HSD11B1, VIP, and UBA6) were regulated by an up-regulated circRNA (circARID1A) via sponging a down-regulated microRNA (miR-204-3p) in human neuronal cells. Particularly, alteration of NLGN1 expression is known to affect the dynamic processes of memory consolidation and strengthening. To the best of our knowledge, this is the first systems-level view of circRNA regulatory networks in ASD cortex samples. We provided a rich set of ASD-associated circRNA candidates and the corresponding circRNA-microRNA-mRNA axes, particularly those involving ASD risk genes. Our findings thus support a role for circRNA dysregulation and the corresponding circRNA-microRNA-mRNA axes in ASD pathophysiology.
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Host-directed treatments for tuberculous meningitis utilizing a multi-platform approach across mouse and human models.
Tuberculous meningitis (TB meningitis) is a major cause of death and neurological deficit despite recommended antibiotic and corticosteroid treatments, primarily due to dysregulated neuroinflammation. Here, we investigate a diverse panel of 12 immunomodulatory drugs as host-directed treatments (HDTs) for TB meningitis utilizing a cross-species framework comprising studies in a mouse model of TB meningitis with clinical endpoints, and parallel mechanistic studies in a newly developed immune-vascularized human brain organoid model of TB meningitis and peripheral blood mononuclear cells (PBMCs) from patients with TB meningitis. Imatinib, bestatin, roflumilast, palacaparib, thalidomide/pomalidomide and semaglutide outperform the current standard of care by reducing mortality and/or neurological deficits in mice via suppression of neuroinflammation. Importantly, these HDTs significantly reduce microglial activation in Mycobacterium tuberculosis-infected human brain organoids and attenuate proinflammatory cytokines, particularly IFNγ within CD4+ T-cells in patient-derived PBMCs. These findings highlight the potential of targeted HDTs to improve outcomes in TB meningitis and warrant clinical investigation.
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Phenotypic, metabolic, and biogenesis properties of human stem cell-derived cerebellar spheroids.
Human cerebellum consists of high density and complexity of neurons. Thus, it is challenging to differentiate cerebellar-like organoids with similar cellular markers and function to the human brain. Our previous study showed that the combination of retinoic acid (RA), Wingless/integrated (Wnt) activator, and Sonic Hedgehog (SHH) activator promotes cerebellar differentiation from human induced pluripotent stem cells (hiPSCs). This study examined phenotypic, metabolic, and biogenesis in early cerebellar development. Cerebellum spheroids were differentiated from human iPSK3 cells. During day 7-14, RA and Wnt activator CHIR99021 were used and SHH activator purmorphamine (PMR) was added later to promote ventralization. Gene expression for early cerebellar layer markers, metabolism, and extracellular vesicle (EV) biogenesis were characterized. Zinc-induced neurotoxicity was investigated as a proof-of-concept of neurotoxicity study. Flow cytometry results showed that there was no significant difference in NEPH3, PTF1A, OLIG2, and MATH1 protein expression between RCP (RA-CHIR-PMR) versus the control condition. However, the expression of cerebellar genes for the molecular layer (BHLE22), the granule cell layer (GABRB2, PAX6, TMEM266, KCNIP4), the Bergmann glial cells (QK1, DAO), and the Purkinje cell layer (ARHGEF33, KIT, MX1, MYH10, PPP1R17, SCGN) was significantly higher in the RCP condition than the control. The shift in metabolic pathways toward glycolysis was observed for RCP condition. The EV biogenesis marker expression was retained. Mild zinc-induced neurotoxicity may exist when zinc exposure exceeds 1.0 µM. RCP treatment can promote specific cerebellar-like differentiation from hiPSCs indicated by gene expression of early cerebellar markers and regionally enriched genes. The higher cerebellar marker expression is accompanied by the elevated glycolysis with the retained EV biogenesis. This study should advance the understanding of biomarkers during early cerebellar development for cerebellum organoid engineering and neurotoxicity study.
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ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease.
APOE4 is the first identified genetic risk factor and remains as the strongest predictor for late-onset Alzheimer's disease (AD). Studies of AD patients, AD patient-specific induced pluripotent stem cell-derived neurons and cerebral organoids, and human apoE4-expressing and apoE-deficient mouse models clearly demonstrate that apoE4 provokes neuroinflammation, impairs cerebrovasculature, and exacerbates amyloid and tau pathologies. ApoE expression is greatly up-regulated in disease-associated microglia in mouse models of amyloidosis and in human microglia from AD brains. Importantly, genetic knock-down or depletion of apoE in mice greatly attenuates neuroinflammation and alleviates amyloid and tau pathologies. Similar beneficial effects can be achieved when apoE reduction is induced by the overexpression of apoE metabolic receptor LDLR. Toward therapeutic implications, administration of apoE antisense oligonucleotides or apoE siRNAs leads to significant pharmacologic effects, i.e., significant alleviation of AD pathologies in mouse models. Therefore, apoE reduction represents a promising therapeutic strategy for the treatment of AD patients carrying the APOE ε4 allele. In this review, we summarize evidence and rationale on why and how we target apoE4 reduction for AD therapy.
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Deoxynivalenol-induced anorexia is mediated by brain-gut peptides through CaSR-TRPM5 signaling axis.
Deoxynivalenol (DON), a secondary metabolite produced by Fusarium, can widely contaminate foods and feeds, endangering human and animal health. DON can cause anorexia in animals. However, the specific mechanism is unclear. In this study, in vivo and in vitro experiments were conducted in mice and mouse intestinal organoid, respectively. Specific antagonists NPS2143, U73122, Xestospongin C, TPPO, EGTA, and Nitrendipine were selected to inhibit CaSR, PLCβ2, IP3R, TRPM5, extracellular calcium, and L-type VSCCs to explore the effect of the CaSR-TRPM5 signaling axis in DON-induced anorexia and secretion of brain-gut peptide. The results showed that these antagonists attenuated the DON-induced anorexia and secretion of the brain-gut peptides CCK, PYY, GLP-1, and GIP. DON could significantly increase the expression of hypothalamic anorectic genes MC4R, POMC, and CART. Blocking the CaSR-TRPM5 signaling axis could attenuate these changes. The mouse small intestinal organoid can be induced to differentiate into EECs by blocking the Wnt/Notch/Mek pathway. DON-induced brain-gut peptides secretion was attenuated by inhibition of CaSR-TRPM5 signaling axis in mouse intestinal organoid. In summary, DON could act on enteroendocrine cells to induce secretion of brain-gut peptide and activate the hypothalamic anorectic genes to evoke anorexia through the CaSR-TRPM5 signaling axis.
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Neurologic manifestations of the organoid nevus syndrome.
Prominent neurologic abnormalities were observed in six patients with epidermal or linear sebaceous nevi (organoid nevi). These cases were remarkable for unilateral facial nevi, cognitive impairment, seizures, and focal or lateralized epileptic EEG abnormalities. Additional manifestations included the onset of seizures in the neonatal period, unilateral hypsarrhythmia or Lennox-Gastaut EEG pattern, hemiparesis, asymmetric macrocephaly, and somatic growth disturbances. The full expression of this disorder was not apparent at birth, but emerged gradually during infancy. The neurologic abnormalities in these patients were attributed to unilateral or asymmetric malformations of the CNS as demonstrated by computed tomography. A lateralized disorder of neuroectodermal proliferation, differentiation, and migration could account for both the cutaneous and neurologic abnormalities in this disorder. The striking clinical similarities in these patients suggest a close link between epidermal and linear sebaceous nevi.
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Short Review: Investigating ARSACS: models for understanding cerebellar degeneration.
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease that includes progressive cerebellar dysfunction. ARSACS is caused by an autosomal recessive loss-of-function mutation in the SACS gene, which encodes for SACSIN. Although animal models are still necessary to investigate the role of SACSIN in the pathology of this disease, more reliable human cellular models need to be generated to better understand the cerebellar pathophysiology of ARSACS. The discovery of human induced pluripotent stem cells (hiPSC) has permitted the derivation of patient-specific cells. These cells have an unlimited self-renewing capacity and the ability to differentiate into different neural cell types, allowing studies of disease mechanism, drug discovery and cell replacement therapies. In this study, we discuss how the hiPSC-derived cerebellar organoid culture offers novel strategies for targeting the pathogenic mutations related to ARSACS. We also highlight the advantages and challenges of this 3D cellular model, as well as the questions that still remain unanswered.
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The dangers of rubella virus.
The rubella virus can interfere with fetal brain development by infecting immune cells called microglia during pregnancy.