Alexander Disease Modeling in Zebrafish: An In Vivo System Suitable to Perform Drug Screening

Candiani, Simona; Carestiato, Silvia; Mack, Andreas F.; Bani, Danièle; Bozzo, Matteo; Obino, Valentina; Ori, Michela; Rosamilia, Francesca; Sarlo, Miriam De; Pestarino, Mario; Ceccherini, Isabella; Bachetti, Tiziana

doi:10.3390/genes11121490

Cited by 5 publications

(1 citation statement)

References 33 publications

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“…Accordingly, these animals also expressed lower levels of the basilar myelin protein constituents (Cnp, Mbp, Mog, Mobp, Mag, and Plp1) [ 79 ] suggesting this model as a useful tool to study AxD myelination defects. Newly generated zebrafish models revealed instead a useful system to study the early stages of disease [ 80 , 81 ], but, overall, these animal models ( Figure 2 ) did not succeed in clarifying the relationship between diseased astrocytes and oligodendrocyte/myelin defects. To investigate further this issue, several laboratories generated astrocytes and oligodendrocyte progenitor cells (OPCs) from AxD patient-derived hiPSC ( Table 1 ).…”

Section: Astrocytopathies: When Myelin Defects Are Caused By Astrocyte Disfunctionsmentioning

confidence: 99%

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

Lanciotti

Brignone

Macioce

et al. 2021

IJMS

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Astrocytes are very versatile cells, endowed with multitasking capacities to ensure brain homeostasis maintenance from brain development to adult life. It has become increasingly evident that astrocytes play a central role in many central nervous system pathologies, not only as regulators of defensive responses against brain insults but also as primary culprits of the disease onset and progression. This is particularly evident in some rare leukodystrophies (LDs) where white matter/myelin deterioration is due to primary astrocyte dysfunctions. Understanding the molecular defects causing these LDs may help clarify astrocyte contribution to myelin formation/maintenance and favor the identification of possible therapeutic targets for LDs and other CNS demyelinating diseases. To date, the pathogenic mechanisms of these LDs are poorly known due to the rarity of the pathological tissue and the failure of the animal models to fully recapitulate the human diseases. Thus, the development of human induced pluripotent stem cells (hiPSC) from patient fibroblasts and their differentiation into astrocytes is a promising approach to overcome these issues. In this review, we discuss the primary role of astrocytes in LD pathogenesis, the experimental models currently available and the advantages, future evolutions, perspectives, and limitations of hiPSC to study pathologies implying astrocyte dysfunctions.

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Section: Astrocytopathies: When Myelin Defects Are Caused By Astrocyte Disfunctionsmentioning

confidence: 99%

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

Lanciotti

Brignone

Macioce

et al. 2021

IJMS

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Response to amoxicillin and perampanel in infantile Alexander disease

Boronat,

Turon‐Viñas,

Mac Manus

et al. 2024

Epilepsia Open

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Type I Alexander disease (AxD) presents with paroxysmal neurodegeneration, refractory epilepsy, and encephalopathy in the first years of life and is associated with a poor prognosis. Although there is no treatment, mild symptomatic improvement has been reported in one case of adult Alexander treated with ceftriaxone, given its interaction with the mutant glial fibrillary acid protein (GFAP) responsible for the disease's pathogenesis. We describe a patient presenting with irritability starting at 2 months of age, initially attributed to gastroesophageal reflux. A ventriculoperitoneal shunt was placed at 3 months of age due to hydrocephalus secondary to aqueduct stenosis detected through an MRI scan, but the irritability persisted. At 5 months, a new brain MRI was performed due to irritability worsening, onset of abnormal ocular movements and seizures. In addition genetic testing was performed. AxD was diagnosed due to the mutation c.716G>A (p.Arg239His) in GFAP. Since irritability had worsened and had not responded to levomepromazine, treatment with amoxicillin (80 mg/kg/day) was attempted to modulate glutamate levels. The patient showed a striking improvement of irritability in 48 h that persisted over the next months. The patient had frequent daily seizures which did not respond to valproate, clonazepam, or phenobarbital. Perampanel, a postsynaptic AMPA receptor antagonist, was added to phenobarbital and he was seizure free for more than 3 months. Drugs modulating glutamate levels in the central nervous system, including β‐lactam antibiotics and perampanel, may have an important role in the symptomatic treatment of AxD and other neurodegenerative diseases where glutamatergic excitotoxicity is a pathogenic determinant.Plain Language SummaryAlexander disease is a rare and serious condition that affects the brain, often leading to neurodegeneration (brain damage), seizures, and other problems in early childhood. The disease is caused by a mutation in a gene called GFAP. There is no cure, and current treatments mainly focus on relieving symptoms. This article discusses the case of a baby who showed signs of irritability and seizures from a young age. The baby was diagnosed with Alexander disease after brain scans and genetic testing. Despite treatment with various drugs, the baby continued to experience seizures and irritability. The doctors decided to try amoxicillin, a common antibiotic, because of its potential to help control the disease by affecting a brain chemical called glutamate. Surprisingly, the baby's irritability improved within 2 days of starting amoxicillin, and the improvement lasted for several months. However, the seizures persisted until another medication, perampanel, was added. This combination controlled the baby's seizures for over 3 months. Unfortunately, the baby passed away at 13 months due to complications from the disease. However, doctors believe that drugs like amoxicillin and perampanel could be promising treatments for managing symptoms of Alexander disease and other similar brain conditions in the future, especially where excess glutamate plays a role in the damage. This case suggests that these treatments may help control irritability and seizures, offering hope for better management of this challenging disease.

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Covalent binding of withanolides to cysteines of protein targets

Bailly

2024

Biochemical Pharmacology

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Alexander Disease Modeling in Zebrafish: An In Vivo System Suitable to Perform Drug Screening

Cited by 5 publications

References 33 publications

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

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

Response to amoxicillin and perampanel in infantile Alexander disease

Covalent binding of withanolides to cysteines of protein targets

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