Human iPSC-Derived Astrocytes: A Powerful Tool to Study Primary Astrocyte Dysfunction in the Pathogenesis of Rare Leukodystrophies

Lanciotti, Angela; Brignone, Maria Stefania; Macioce, Pompeo; Visentin, Sergio; Ambrosini, Elena

doi:10.3390/ijms23010274

Cited by 8 publications

(7 citation statements)

References 204 publications

(252 reference statements)

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“…R79 and R239 were the most common early-onset types of AxD; however, patients with R88 and R416 did not present a significant genotype–phenotype correlation ( 14 , 23 ). Astrocytes differentiated from patients carrying R88C by displaying changes in intracellular vesicle transport, calcium dynamics, and adenosine triphosphate (ATP) release ( 26 ). Our patient had a mutation at R88 of GFAP, a pathogenic mutation that could lead to the 88th amino acid change from arginine to cysteine.…”

Section: Discussionmentioning

confidence: 99%

Case report: Alexander's disease with “head drop” as the main symptom and literature review

Yuan

Huang

et al. 2022

Front. Neurol.

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Alexander's disease (AxD) is a rare autosomal dominant hereditary disorder that is caused by the mutations in the GFAP gene, which encodes the glial fibrillary acidic protein (GFAP). This neurogenerative disease has many clinical manifestations, and the onset of disease spans a wide range of ages, from newborns to children, adults, and even the elderly. An overaccumulation of the expression of GFAP has a close causal relationship with the pathogenesis of Alexander's disease. Usually, the disease has severe morbidity and high mortality, and can be divided into three distinct subgroups that are based on the age of clinical presentation: infantile (0–2 years), juvenile (2–13 years), and adult (>13 years). Children often present with epilepsy, macrocephaly, and psychomotor retardation, while adolescents and adults mainly present with muscle weakness, spasticity, and bulbar symptoms. Atonic seizures are a type of epilepsy that often appears in the Lennox–Gastaut syndrome and myoclonic–astatic epilepsy in early childhood; however, the prognosis is often poor. Atonic episodes are characterized by a sudden or frequent reduction in muscle tone that can be local (such as head, neck, or limb) or generalized. Here, we report a 4-year-old girl whose main symptoms were intermittent head drop movements, which could break the frontal frame and even bleed in severe conditions. A video-encephalography (VEEG) showed that the nodding movements were atonic seizures. A head magnetic resonance imaging (MRI) revealed abnormal signals in the bilateral paraventricular and bilateral subfrontal cortex. The gene detection analyses indicated that the GFAP gene exon 1 c.262 C>T was caused by a heterozygous mutation, as both her parents were of the wild-type. The girl had no other abnormal manifestations except atonic seizures. She could communicate normally and go to kindergarten. After an oral administration of sodium valproate, there were no atonic attacks. Although epilepsy is a common symptom of Alexander's disease, atonic seizures have not been reported to date. Therefore, we report a case of Alexander's disease with atonic seizures as the main symptom and provide a review of the literature.

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Section: Discussionmentioning

confidence: 99%

Case report: Alexander's disease with “head drop” as the main symptom and literature review

Yuan

Huang

et al. 2022

Front. Neurol.

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“…Historically, these pathologies have been attributed to impacted oligodendrocytes and neuronal axons of the white matter. However, fibrous astrocytes are now garnering increased attention as key regulators and possibly, therapeutic targets of white matter disorders 155 …”

Section: Astrocytic Dysfunction As the Basis For Neurobehavioral Diso...mentioning

confidence: 99%

Astrocytes as master modulators of neural networks: Synaptic functions and disease‐associated dysfunction of astrocytes

Stogsdill

Harwell

Goldman

2023

Annals of the New York Academy of Sciences

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Astrocytes are the most abundant glial cell type in the central nervous system and are essential to the development, plasticity, and maintenance of neural circuits. Astrocytes are heterogeneous, with their diversity rooted in developmental programs modulated by the local brain environment. Astrocytes play integral roles in regulating and coordinating neural activity extending far beyond their metabolic support of neurons and other brain cell phenotypes. Both gray and white matter astrocytes occupy critical functional niches capable of modulating brain physiology on time scales slower than synaptic activity but faster than those adaptive responses requiring a structural change or adaptive myelination. Given their many associations and functional roles, it is not surprising that astrocytic dysfunction has been causally implicated in a broad set of neurodegenerative and neuropsychiatric disorders. In this review, we focus on recent discoveries concerning the contributions of astrocytes to the function of neural networks, with a dual focus on the contribution of astrocytes to synaptic development and maturation, and on their role in supporting myelin integrity, and hence conduction and its regulation. We then address the emerging roles of astrocytic dysfunction in disease pathogenesis and on potential strategies for targeting these cells for therapeutic purposes.

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“…Astrocytopathies including Alexander disease[ 37 , 38 ], Aicardi-Goutières syndrome (AGS)[ 39 ], and vanishing white matter disease[ 40 ] can be effectively modeled with hiPSC-derived astrocytes[ 41 ]. Neurodegenerative diseases including Alzheimer’s disease (AD)[ 36 ], Parkinson’s disease (PD)[ 42 ], and Huntington’s disease have also been modeled using similar methods. The familial presenilin-1 ( PS1 ) mutation along with PD familial leucine-rich repeat kinase 2 ( LRRK2 ) G2019S mutations were both modeled using hiPSC-derived astrocytes.…”

Section: Neural Cell Type Differentiation From Hpscsmentioning

confidence: 99%

Neural lineage differentiation of human pluripotent stem cells: Advances in disease modeling

Yan¹,

Qian²,

Woodard³

et al. 2023

World J Stem Cells

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Brain diseases affect 1 in 6 people worldwide. These diseases range from acute neurological conditions such as stroke to chronic neurodegenerative disorders such as Alzheimer’s disease. Recent advancements in tissue-engineered brain disease models have overcome many of the different shortcomings associated with the various animal models, tissue culture models, and epidemiologic patient data that are commonly used to study brain disease. One innovative method by which to model human neurological disease is via the directed differentiation of human pluripotent stem cells (hPSCs) to neural lineages including neurons, astrocytes, and oligodendrocytes. Three-dimensional models such as brain organoids have also been derived from hPSCs, offering more physiological relevance due to their incorporation of various cell types. As such, brain organoids can better model the pathophysiology of neural diseases observed in patients. In this review, we will emphasize recent developments in hPSC-based tissue culture models of neurological disorders and how they are being used to create neural disease models.

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Human iPSC-Derived Astrocytes: A Powerful Tool to Study Primary Astrocyte Dysfunction in the Pathogenesis of Rare Leukodystrophies

Cited by 8 publications

References 204 publications

Case report: Alexander's disease with “head drop” as the main symptom and literature review

Case report: Alexander's disease with “head drop” as the main symptom and literature review

Astrocytes as master modulators of neural networks: Synaptic functions and disease‐associated dysfunction of astrocytes

Neural lineage differentiation of human pluripotent stem cells: Advances in disease modeling

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