Cerebral Organoids—Challenges to Establish a Brain Prototype

Eremeev, A V; Lebedeva, Olga; Bogomiakova, Margarita E.; Lagarkova, Maria A.; Bogomazova, Alexandra N.

doi:10.3390/cells10071790

Cited by 15 publications

(11 citation statements)

References 134 publications

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“…Recently, in vitro experiments came to be performed on several HD patient-derived cell lines, such as fibroblast-derived cell lines or pluripotent stem cell lines, which can be differentiated into neural precursor cells [ 40 , 41 ]. In an attempt to overcome the limitations of two-dimensional culture experiments and to mimic the intercellular signaling and circuitry of the human brain, cerebral organoids (“minibrains”) derived from patient-induced pluripotent stem cells were developed and are useful tools in research [ 42 , 43 ].…”

Section: Models Of Hdmentioning

confidence: 99%

Molecular Pathophysiological Mechanisms in Huntington’s Disease

Jurcău

2022

Biomedicines

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Huntington’s disease is an inherited neurodegenerative disease described 150 years ago by George Huntington. The genetic defect was identified in 1993 to be an expanded CAG repeat on exon 1 of the huntingtin gene located on chromosome 4. In the following almost 30 years, a considerable amount of research, using mainly animal models or in vitro experiments, has tried to unravel the complex molecular cascades through which the transcription of the mutant protein leads to neuronal loss, especially in the medium spiny neurons of the striatum, and identified excitotoxicity, transcriptional dysregulation, mitochondrial dysfunction, oxidative stress, impaired proteostasis, altered axonal trafficking and reduced availability of trophic factors to be crucial contributors. This review discusses the pathogenic cascades described in the literature through which mutant huntingtin leads to neuronal demise. However, due to the ubiquitous presence of huntingtin, astrocytes are also dysfunctional, and neuroinflammation may additionally contribute to Huntington’s disease pathology. The quest for therapies to delay the onset and reduce the rate of Huntington’s disease progression is ongoing, but is based on findings from basic research.

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Section: Models Of Hdmentioning

confidence: 99%

Molecular Pathophysiological Mechanisms in Huntington’s Disease

Jurcău

2022

Biomedicines

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“…Following the identification of the genetic defect, many groups of researchers, using chemical models [ 6 ], various genetic animal models [ 7 ], or complex cell lines mimicking the intercellular signaling and circuitry of the human brain [ 8 ], focused on unraveling the complex mechanisms through which the expression of an abnormal protein (mutant huntingtin, mHtt) leads to the massive cellular degeneration and the loss of synaptic activity in HD. Several vicious pathways have been identified [ 5 ], but the detailed description of these pathways is beyond the scope of this review, which is why they will be only briefly summarized below.…”

Section: Pathophysiology Of Huntington’s Diseasementioning

confidence: 99%

Therapeutic Strategies in Huntington’s Disease: From Genetic Defect to Gene Therapy

Jurcău

2022

Biomedicines

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Despite the identification of an expanded CAG repeat on exon 1 of the huntingtin gene located on chromosome 1 as the genetic defect causing Huntington’s disease almost 30 years ago, currently approved therapies provide only limited symptomatic relief and do not influence the age of onset or disease progression rate. Research has identified various intricate pathogenic cascades which lead to neuronal degeneration, but therapies interfering with these mechanisms have been marked by many failures and remain to be validated. Exciting new opportunities are opened by the emerging techniques which target the mutant protein DNA and RNA, allowing for “gene editing”. Although some issues relating to “off-target” effects or immune-mediated side effects need to be solved, these strategies, combined with stem cell therapies and more traditional approaches targeting specific pathogenic cascades, such as excitotoxicity and bioavailability of neurotrophic factors, could lead to significant improvement of the outcomes of treated Huntington’s disease patients.

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“…Given the focus of the current special issue it is anticipated that many of these model systems proposed for neurotoxicity assessment will be discussed in methodological detail in other articles. Additionally, critical reviews covering the benefits and limitations of such systems in modeling the brain environment and translating to use for human disorders are available ( Barbosa et al, 2015 ; Young-Pearse and Morrow, 2016 ; Fink and Levine, 2018 ; Chen et al, 2019 ; Oliveira et al, 2019 ; Gordon and Geschwind, 2020 ; Lee et al, 2020 ; Slanzi et al, 2020 ; Eremeev et al, 2021 ; Franklin et al, 2021 ; Xu and Wen, 2021 ). Of equal importance of evaluating their benefits and limitations is the opportunity to mesh the in vitro and non-mammalian approaches with the mammalian models to develop a more integrated approach for assessment.…”

Section: In Vitro Model Systems In Neurotoxicity Assessmentmentioning

confidence: 99%

Roadbumps at the Crossroads of Integrating Behavioral and In Vitro Approaches for Neurotoxicity Assessment

Harry¹,

McBride²,

Witchey³

et al. 2022

Front. Toxicol.

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With the appreciation that behavior represents the integration and complexity of the nervous system, neurobehavioral phenotyping and assessment has seen a renaissance over the last couple of decades, resulting in a robust database on rodent performance within various testing paradigms, possible associations with human disorders, and therapeutic interventions. The interchange of data across behavior and other test modalities and multiple model systems has advanced our understanding of fundamental biology and mechanisms associated with normal functions and alterations in the nervous system. While there is a demonstrated value and power of neurobehavioral assessments for examining alterations due to genetic manipulations, maternal factors, early development environment, the applied use of behavior to assess environmental neurotoxicity continues to come under question as to whether behavior represents a sensitive endpoint for assessment. Why is rodent behavior a sensitive tool to the neuroscientist and yet, not when used in pre-clinical or chemical neurotoxicity studies? Applying new paradigms and evidence on the biological basis of behavior to neurobehavioral testing requires expertise and refinement of how such experiments are conducted to minimize variability and maximize information. This review presents relevant issues of methods used to conduct such test, sources of variability, experimental design, data analysis, interpretation, and reporting. It presents beneficial and critical limitations as they translate to the in vivo environment and considers the need to integrate across disciplines for the best value. It proposes that a refinement of behavioral assessments and understanding of subtle pronounced differences will facilitate the integration of data obtained across multiple approaches and to address issues of translation.

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Cerebral Organoids—Challenges to Establish a Brain Prototype

Cited by 15 publications

References 134 publications

Molecular Pathophysiological Mechanisms in Huntington’s Disease

Molecular Pathophysiological Mechanisms in Huntington’s Disease

Therapeutic Strategies in Huntington’s Disease: From Genetic Defect to Gene Therapy

Roadbumps at the Crossroads of Integrating Behavioral and In Vitro Approaches for Neurotoxicity Assessment

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