Cortical assembloids support the development of fast-spiking human PVALB+ cortical interneurons and uncover schizophrenia-associated defects.

Disruption of parvalbumin positive (PVALB+) cortical interneurons is implicated in the pathogenesis of schizophrenia. However, how these defects emerge during brain development remains poorly understood. The protracted maturation of these cells during postnatal life has made their derivation from human pluripotent stem cells (hPSCs) extremely difficult, precluding hPSC-based disease modeling of their role in neuropsychiatric disease.

SARS-CoV-2 infection causes dopaminergic neuron senescence.

COVID-19 patients commonly present with signs of central nervous system and/or peripheral nervous system dysfunction. Here, we show that midbrain dopamine (DA) neurons derived from human pluripotent stem cells (hPSCs) are selectively susceptible and permissive to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. SARS-CoV-2 infection of DA neurons triggers an inflammatory and cellular senescence response.

ZCCHC17 Modulates Neuronal RNA Splicing and Supports Cognitive Resilience in Alzheimer's Disease.

ZCCHC17 is a putative master regulator of synaptic gene dysfunction in Alzheimer's disease (AD), and ZCCHC17 protein declines early in AD brain tissue, before significant gliosis or neuronal loss. Here, we investigate the function of ZCCHC17 and its role in AD pathogenesis using data from human autopsy tissue (consisting of males and females) and female human cell lines. Co-immunoprecipitation (co-IP) of ZCCHC17 followed by mass spectrometry analysis in human iPSC-derived neurons reveals that ZCCHC17's binding partners are enriched for RNA-splicing proteins.

ZCCHC17 modulates neuronal RNA splicing and supports cognitive resilience in Alzheimer's disease.

ZCCHC17 is a putative master regulator of synaptic gene dysfunction in Alzheimer's Disease (AD), and ZCCHC17 protein declines early in AD brain tissue, before significant gliosis or neuronal loss. Here, we investigate the function of ZCCHC17 and its role in AD pathogenesis. Co-immunoprecipitation of ZCCHC17 followed by mass spectrometry analysis in human iPSC-derived neurons reveals that ZCCHC17's binding partners are enriched for RNA splicing proteins.

Aβ42 oligomers trigger synaptic loss through CAMKK2-AMPK-dependent effectors coordinating mitochondrial fission and mitophagy.

During the early stages of Alzheimer's disease (AD) in both mouse models and human patients, soluble forms of Amyloid-β 1-42 oligomers (Aβ42o) trigger loss of excitatory synapses (synaptotoxicity) in cortical and hippocampal pyramidal neurons (PNs) prior to the formation of insoluble amyloid plaques. In a transgenic AD mouse model, we observed a spatially restricted structural remodeling of mitochondria in the apical tufts of CA1 PNs dendrites corresponding to the dendritic domain where the earliest synaptic loss is detected in vivo. We also observed AMPK over-activation as well as increased fragmentation and loss of mitochondrial biomass in Ngn2-induced neurons derived from a new APP knockin human ES cell line.

SARS-CoV-2 Infection Causes Dopaminergic Neuron Senescence.

COVID-19 patients commonly present with neurological signs of central nervous system (CNS) and/or peripheral nervous system dysfunction. However, which neural cells are permissive to infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been controversial. Here, we show that midbrain dopamine (DA) neurons derived from human pluripotent stem cells (hPSCs) are selectively permissive to SARS-CoV-2 infection both and upon transplantation , and that SARS-CoV-2 infection triggers a DA neuron inflammatory and cellular senescence response.

Biphasic Activation of WNT Signaling Facilitates the Derivation of Midbrain Dopamine Neurons from hESCs for Translational Use.

Human pluripotent stem cells show considerable promise for applications in regenerative medicine, including the development of cell replacement paradigms for the treatment of Parkinson's disease. Protocols have been developed to generate authentic midbrain dopamine (mDA) neurons capable of reversing dopamine-related deficits in animal models of Parkinson's disease. However, the generation of mDA neurons at clinical scale suitable for human application remains an important challenge.

Pluripotent Stem Cell Therapies for Parkinson Disease: Present Challenges and Future Opportunities.

In Parkinson's disease (PD), there are currently no effective therapies to prevent or slow down disease progression. Cell replacement therapy using human pluripotent stem cell (hPSC)-derived dopamine neurons holds considerable promise. It presents a novel, regenerative strategy, building on the extensive history of fetal tissue grafts and capturing the potential of hPSCs to serve as a scalable and standardized cell source.

The Alzheimer's disease-associated C99 fragment of APP regulates cellular cholesterol trafficking.

The link between cholesterol homeostasis and cleavage of the amyloid precursor protein (APP), and how this relationship relates to Alzheimer's disease (AD) pathogenesis, is still unknown. Cellular cholesterol levels are regulated through crosstalk between the plasma membrane (PM), where most cellular cholesterol resides, and the endoplasmic reticulum (ER), where the protein machinery that regulates cholesterol levels resides. The intracellular transport of cholesterol from the PM to the ER is believed to be activated by a lipid-sensing peptide(s) in the ER that can cluster PM-derived cholesterol into transient detergent-resistant membrane domains (DRMs) within the ER, also called the ER regulatory pool of cholesterol.

CRISPR/Cas9 editing of APP C-terminus attenuates β-cleavage and promotes α-cleavage.

CRISPR/Cas9 guided gene-editing is a potential therapeutic tool, however application to neurodegenerative disease models has been limited. Moreover, conventional mutation correction by gene-editing would only be relevant for the small fraction of neurodegenerative cases that are inherited. Here we introduce a CRISPR/Cas9-based strategy in cell and animal models to edit endogenous amyloid precursor protein (APP) at the extreme C-terminus and reciprocally manipulate the amyloid pathway, attenuating APP-β-cleavage and Aβ production, while up-regulating neuroprotective APP-α-cleavage.

Reducing eIF4E-eIF4G interactions restores the balance between protein synthesis and actin dynamics in fragile X syndrome model mice.

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and autism spectrum disorder. FXS is caused by silencing of the gene, which encodes fragile X mental retardation protein (FMRP), an mRNA-binding protein that represses the translation of its target mRNAs. One mechanism by which FMRP represses translation is through its association with cytoplasmic FMRP-interacting protein 1 (CYFIP1), which subsequently sequesters and inhibits eukaryotic initiation factor 4E (eIF4E).

eIF4E/Fmr1 double mutant mice display cognitive impairment in addition to ASD-like behaviors.

Autism spectrum disorder (ASD) is a group of heritable disorders with complex and unclear etiology. Classic ASD symptoms include social interaction and communication deficits as well as restricted, repetitive behaviors. In addition, ASD is often comorbid with intellectual disability.

Decreased dendritic spine density and abnormal spine morphology in Fyn knockout mice.

Fyn is a Src-family tyrosine kinase that affects long term potentiation (LTP), synapse formation, and learning and memory. Fyn is also implicated in dendritic spine formation both in vitro and in vivo. However, whether Fyn's regulation of dendritic spine formation is brain-region specific and age-dependent is unknown.

Plant growth-promoting trait of rhizobacteria isolated from soil contaminated with petroleum and heavy metals.

Three hundred and seventy-four rhizobacteria were isolated from the rhizosphere soil (RS) or rhizoplane (RP) of Echinochloa crus-galli, Carex leiorhyncha, Commelina communis, Persicaria lapathifolia, Carex kobomugi, and Equisetum arvense, grown in contaminated soil with petroleum and heavy metals. The isolates were screened for plant growth-promoting potential (PGPP), including indole acetic acid (IAA) productivity, 1-aminocyclopropane-1-carboxylic acid (ACC) deaminase activity, and siderophore(s) synthesis ability. IAA production was detected in 86 isolates (23.

Isolation and characterization of a plant growth-promoting rhizobacterium, Serratia sp. SY5.

The role of plant growth-promoting rhizobacteria (PGPR) in the phytoremediation of heavy-metal-contaminated soils is important in overcoming its limitations for field application. A plant growth-promoting rhizobacterium, Serratia sp. SY5, was isolated from the rhizoplane of barnyard grass (Echinochloa crus-galli) grown in petroleum and heavy-metal-contaminated soil.