Topic: induced pluripotent stem cells

Human sleep is a complex physiological process necessary for the organisms’ restoration and the correct functioning of the brain. Insufficient sleep is an under-reported epidemic with sleep disturbances being common early signs of neurodegeneration, in particular of Parkinson’s Disease (PD). Clinical research is currently challenging the assumption that human sleep is a one-fits-all phenomenon: breaking new grounds into sleep research is needed. In this scenario, the European Research Council PathFinder Open project NAP proposes a new science-toward-technology paradigm enabling the study of hu

Dopaminergic neuron cell death in Parkinson’s Disease (PD) is complex and combinatorial, with impairments in multiple cellular pathways impacting mitochondrial function, endosomal/lysosomal protein degradation, alpha-synuclein and tau aggregation, and neuroinflammation. Genetic risk factors, such as mutations in leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GBA), have been shown to impact kinetics of the autophagiclysosomal pathway (ALP), which is suggested to contribute to PD-associated protein accumulation and aggregation. Human-relevant in vitro models using patient-derived i

Studying human brain development has remained difficult as appropriate models lack. Recently, induced pluripotent stem cells (iPSC)-derived 3D brain organoids have been developed. They recapitulate the key aspects of human brain development such as the cellular complexity and functional properties of specific regions. Yet, longitudinal functional studies are sparse. During neurodevelopment in vivo, GABAergic inhibitory interneurons from the ventral cortex migrate to populate the dorsal part of the cortex enriched in glutamatergic excitatory neurons (Zhu et al. Neuron, 1999; Le et al., JBC, 200

Fragile X Syndrome (FXS), the most common hereditary cause of intellectual disability and autism spectrum disorder, is caused by the lack of expression of the Fragile X messenger ribonucleoprotein 1 (FMRP). FMRP is a widely expressed RNA-binding protein that plays a pivotal role in regulating protein synthesis. The absence of its expression has been linked to abnormal synaptic transmission and improper dendritic spines morphogenesis, which are tough to underlies the bulk of the cognitive and behavioral defects exhibited by FXS patients. However, our current understanding of FXS physiopathology

Autism Spectrum Disorder (ASD) is characterized mainly by social and sensory-motor abnormal and repetitive behavior patterns. Over hundreds of genes and thousands of genetic variants were reported to be highly penetrant and causative of ASD. Many of these mutations cause comorbidities such as epilepsy and intellectual disabilities (ID). In this study, we measured cortical neurons derived from induced pluripotent stem cells (iPSCs) of patients with four mutations in the genes GRIN2B, SHANK3, UBTF, as well as chromosomal duplication in the 7q11.23 region and compared them to neurons derived from

Autism spectrum disorder (ASD) is a complex and highly prevalent neurodevelopmental disorder. ASD exhibits significant heterogeneity in genotypes and phenotypes. In recent years, dysregulation of protein synthesis has emerged as a converging mechanism in ASD. Here, to explore altered translation in ASD, we used induced pluripotent stem cells (iPSCs) which have emerged as a promising cellular tool for disease modeling. Patient relevant mutations in FMR1, PTEN, and TSC2, that cause dysregulated protein synthesis, were introduced into iPSCs derived from healthy donors via CRISPR/Cas9. Then, iPSCs

FOXG1 is a transcription factor essential for brain development. Mutations in FOXG1 perturb forebrain development and are commonly associated with neurodevelopmental conditions such as autism and epilepsy. These conditions often also co-occur and preliminary studies have suggested a convergent aetiology. Thus studying the biological functions of FOXG1 and providing mechanistic insight into its functions can better reveal the molecular and cellular aetiology of these conditions. This will help us accelerate biomarker discovery and therapeutic strategies for epilepsy in individuals with or witho

Amyotrophic lateral sclerosis (ALS) is an incurable disease of the motoric nervous system characterized by loss of function and degeneration of upper and lower motoneurons. Models resembling clinics are required to study pathomechanisms and validate therapeutic options in ALS. Here, we reprogrammed fibroblasts from ALS patient carrying a mutation in Fused in Sarcoma (FUS) gene into induced pluripotent stem cells (iPSCs). An isogenic iPSC line was generated to serve as a control. Doxycycline-inducible NIL-cassette was introduced for motoneuron differentiation. Motoneurons were analyzed for

The human brain is an extremely complex network of ~80 billion neurons, and it underpins all thoughts and emotions through coordinated neural activity. The underlying network changes with age and environment, and it is vulnerable to perturbations. Our goal is to understand both normal and pathological neural networks at the level of individual neurons, and how human illnesses affect them.Studying human neurodevelopmental disorders is often challenging using animal models. By using cerebral organoids from induced pluripotent stem cells (iPS), we can investigate these conditions in sophisticated

Neuroinflammation, which refers to the inflammatory response occurring in various Central Nervous System (CNS) disorders, is a relatively recent concept. It involves two main types of cells: astrocytes, which play a significant role in the process, and brain myeloid cells (BMC), crucial players in neuroinflammation.Studies examining the entire genome (GWAS) have pinpointed over 30 genetic loci associated with Alzheimer's disease (AD), many of which relate to innate immunity and the function of microglia, notably the apolipoprotein E (APOE) gene. APOE4 is particularly significant, being the str

Alzheimer's disease (AD) is characterized by neurodegeneration due to an accumulation of abnormal amounts of neurodegenerative proteins (NP). Elevated levels of NP have also been observed in patients suffering from temporal lobe epilepsy (TLE) which brings neurodegeneration into association with an increased risk of epileptic seizures. This study aimed to provide pilot data on the possible relationship between excitability and neurodegeneration. Electrical activity was recorded at 37°C using the multielectrode array (MEA) technique in cerebral organoids prepared from induced pluripotent stem c

Patients with mutations in the PRRT2 gene (proline-rich transmembrane protein 2) are characterized by a large spectrum of neurological disorders, including mainly benign epilepsy and paroxysmal kinesigenic dyskinesia. PRRT2 is a neuronal protein implicated in the modulation of the voltage-gated sodium channel, in particular NaV 1.2 and 1.6. Indeed, a dysregulation of this gene could lead to hyperexcitability due to the loss of the Na+ channel modulation. To better understand the mechanism, we generated glutamatergic induced neurons (glutamatergic iNeurons) from PRRT2 induced pluripotent stem c

CDKL5 deficiency disorder (CDD) is an X-linked neurodevelopmental disorder caused by mutations in the CDKL5 gene. CDD is characterized by early-onset epilepsy, global developmental delay, intellectual disability, autistic features, visual impairment, and motor impairment. The CDKL5 gene is located on the X-chromosome and is highly expressed in the forebrain. Despite some molecular and cellular functions of CDKL5 being revealed, gaps and controversies still exist between different studies. The molecular actions of CDKL5 in human-derived neurons and the effects of CDKL5 disruption remain unclear

The Angelman Syndrome (AS) is a rare neurodevelopmental disorder caused by the loss of the maternally expressed UBE3A gene, which encodes an E3 ubiquitin ligase. Although considerable efforts have been put to dissect UBE3A function in the brain, the pathogenic mechanisms remain largely unknown and effective treatments are not available yet. Being an E3 ubiquitin ligase, defective ubiquitination, which may occur in either nuclear or cytosolic compartments, is thought to be a primary mechanism underlying synaptic dysfunction in AS. Increasing evidence indicates a tight functional interplay betwe

Koolen-de Vries syndrome (KdVS), also known as 17q21.31 microdeletion syndrome, is a rare neurodevelopmental disorder characterized by developmental delay, intellectual disability, and congenital malformations in multiple organ systems, including the brain. KdVS is caused by haploinsufficiency of KANSL1, a gene encoding a protein involved in chromatin remodeling during interphase and microtubule stabilisation during mitosis. KANSL1 is widely expressed in early development, but its role in early brain formation is not characterized. Using patient and genetically-edited induced pluripotent stem

Smith Magenis syndrome (SMS) is a rare neurodevelopmental disorder resulting from a microdeletion on chromosomal region 17p11.2, which includes the Retinoic acid-induced 1 (RAI1) gene. Individuals with SMS exhibit a spectrum of psychiatric and neurological manifestations, such as developmental delays, behavioral disturbances, an intellectual disability (ID), and a circadian disorder. Additionally, they may present symptoms typical of Parkinsonism. Despite the availability of rodent models for SMS, the lack of cellular models and potential treatments has limited an in-depth study. In this resea

Developmental and epileptic encephalopathies (DEE) are a spectrum of severe neurological disorders with poorly understood aetiologies, often involving metabolic dysfunctions. Biallelic recessive pathogenic variants in the Solute carrier family 13 member 5 gene (SLC13A5) gene cause a severe form of DEE, characterized by intractable neonatal seizures, developmental delay, and tooth hypoplasia. SLC13A5 encodes the sodium-dependent citrate transporter (NaCT) on the plasma membrane, expressed in brain and liver. Recent investigations highlighted the relevance of NaCT in citrate uptake, influencing

We successfully generated in vitro human regenerative macrophage self-trasplantation (REMaST®) derived from blood monocytes. Transcriptomic analysis of REMaST® confirm the upregulation, compared to M2 macrophages of neurogenic genes, and related to functions required to wound healing including, ECM-remodelling, angiogenesis, response to hypoxia, immune modulation, detoxification and defence, response to stress, and glucose metabolism. Therefore, we decided to exploit REMaST® neuro-regenerative potential and validate these properties. To evaluate REMaST® neurotrophic and neuroprotective activit