Loss of functional System x-c uncouples aberrant postnatal neurogenesis from epileptogenesis in the hippocampus of Kcna1-KO mice

Aloi, Macarena S.; Thompson, Samantha J.; Quartapella, Nicholas; Noebels, Jeffrey L.

doi:10.1016/j.celrep.2022.111696

Cited by 7 publications

(9 citation statements)

References 52 publications

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“…Studies in mouse models provide support for the ability of genetic modifiers to significantly alter the clinical presentation of KCNA1-related channelopathy. At least six genes have been identified that can modify epilepsy phenotypes in the Kcna1 global knockout (KO) mouse model including Cacna1a (a P/Q-type calcium channel α subunit gene) [94]; Mapt (a tau microtubule-binding protein gene) [95]; Bad (a BCL2-associated agonist of cell death gene) [96]; Scn2a (a Nav1.2 voltage-gated sodium channel gene) [97]; Scn8a (a Nav1.6 voltage-gated sodium channel gene) [98]; and Slc7a11 (a System x-c glutamate antiporter gene) [99] (Table 3). These genetic modifiers usually exhibit a reduction in seizures and/or the incidence of sudden unexpected death in epilepsy (SUDEP) in Kcna1 KO mice.…”

Section: Findings In Mouse Modelsmentioning

confidence: 99%

“…In a study exploring the efficacy of anti-sense oligonucleotide (ASO) therapy for the treatment of epilepsy, a reduction in Scn8a brain expression levels by ASO was found to extend the lifespan and delay SUDEP onset in Kcna1 KO mice; however, seizure burden was not significantly improved [98]. In a second study, Slc7a11; Kcna1 double KO animals were generated to investigate mechanisms of neurogenesis and epileptogenesis [99]. Genetic knockout of Slc7a11 was found to have unique modifying effects in Kcna1 KO mice, improving the megencephaly phenotype associated with Kcna1 deletion but not significantly changing seizure severity or SUDEP incidence [99].…”

Section: Findings In Mouse Modelsmentioning

confidence: 99%

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Novel Genetic Variants Expand the Functional, Molecular, and Pathological Diversity of KCNA1 Channelopathy

Paulhus

Glasscock

2023

IJMS

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The KCNA1 gene encodes Kv1.1 voltage-gated potassium channel α subunits, which are crucial for maintaining healthy neuronal firing and preventing hyperexcitability. Mutations in the KCNA1 gene can cause several neurological diseases and symptoms, such as episodic ataxia type 1 (EA1) and epilepsy, which may occur alone or in combination, making it challenging to establish simple genotype–phenotype correlations. Previous analyses of human KCNA1 variants have shown that epilepsy-linked mutations tend to cluster in regions critical for the channel’s pore, whereas EA1-associated mutations are evenly distributed across the length of the protein. In this review, we examine 17 recently discovered pathogenic or likely pathogenic KCNA1 variants to gain new insights into the molecular genetic basis of KCNA1 channelopathy. We provide the first systematic breakdown of disease rates for KCNA1 variants in different protein domains, uncovering potential location biases that influence genotype–phenotype correlations. Our examination of the new mutations strengthens the proposed link between the pore region and epilepsy and reveals new connections between epilepsy-related variants, genetic modifiers, and respiratory dysfunction. Additionally, the new variants include the first two gain-of-function mutations ever discovered for KCNA1, the first frameshift mutation, and the first mutations located in the cytoplasmic N-terminal domain, broadening the functional and molecular scope of KCNA1 channelopathy. Moreover, the recently identified variants highlight emerging links between KCNA1 and musculoskeletal abnormalities and nystagmus, conditions not typically associated with KCNA1. These findings improve our understanding of KCNA1 channelopathy and promise to enhance personalized diagnosis and treatment for individuals with KCNA1-linked disorders.

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Section: Findings In Mouse Modelsmentioning

confidence: 99%

Section: Findings In Mouse Modelsmentioning

confidence: 99%

Novel Genetic Variants Expand the Functional, Molecular, and Pathological Diversity of KCNA1 Channelopathy

Paulhus

Glasscock

2023

IJMS

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“…Studies in mouse models provide support for the ability of genetic modifiers to significantly alter the clinical presentation of KCNA1-related channelopathy. At least 6 genes have been identified that can modify epilepsy phenotypes in the Kcna1 global knockout (KO) mouse model including: Cacna1a (P/Q-type calcium channel α subunit gene) [93]; Mapt (tau microtubule-binding protein gene) [94]; Bad (BCL2-associated agonist of cell death gene) [95]; Scn2a (Nav1.2 voltage-gated sodium channel gene) [96]; Scn8a (Nav1.6 voltage-gated sodium channel gene) [97]; and Slc7a11 (System x-c glutamate antiporter gene) [98] (Table 3). These genetic modifiers usually exhibit a reduction in seizures and/or the incidence of sudden unexpected death in epilepsy (SUDEP) in Kcna1 KO mice.…”

Section: Findings In Mouse Modelsmentioning

confidence: 99%

“…In a study exploring the efficacy of anti-sense oligonucleotide (ASO) therapy for treatment of epilepsy, reduction of Scn8a brain expression levels by ASO was found to extend lifespan and delay SUDEP onset in Kcna1 KO mice; however, seizure burden was not significantly improved [97]. In a second study, Slc7a11; Kcna1 double KO animals were generated to investigate mechanisms of neurogenesis and epileptogenesis [98]. Genetic knockout of Slc7a11 was found to have unique modifying effects in Kcna1 KO mice, improving the megencephaly phenotype associated with Kcna1 deletion but not significantly changing seizure severity or SUDEP incidence [98].…”

Section: Findings In Mouse Modelsmentioning

confidence: 99%

“…In a second study, Slc7a11; Kcna1 double KO animals were generated to investigate mechanisms of neurogenesis and epileptogenesis [98]. Genetic knockout of Slc7a11 was found to have unique modifying effects in Kcna1 KO mice, improving the megencephaly phenotype associated with Kcna1 deletion but not significantly changing seizure severity or SUDEP incidence [98]. Thus, the Slc7a11 mutation seems to have beneficial effects on aberrant postnatal neurogenesis in Kcna1 KO mice without significantly altering epileptogenesis.…”

Section: Findings In Mouse Modelsmentioning

confidence: 99%

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Novel Genetic Variants Expand the Functional, Molecular and Pathological Diversity of KCNA1 Channelopathy

Paulhus¹,

Glasscock²

2023

Preprint

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The KCNA1 gene encodes Kv1.1 voltage-gated potassium channel α subunits, which are crucial for maintaining healthy neuronal firing and preventing hyperexcitability. Mutations in the KCNA1 gene can cause several neurological diseases and symptoms, such as episodic ataxia and epilepsy, which may occur alone or in combination, making it challenging to establish simple genotype-phenotype correlations. Previous analyses of human KCNA1 variants have shown that epilepsy-linked mutations tend to cluster in regions critical for the channel’s pore, whereas EA1-associated mutations are evenly distributed across the length of the protein. In this review, we examine 17 recently discovered pathogenic or likely pathogenic KCNA1 variants to gain new insights into the molecular genetic basis of KCNA1 channelopathy. We provide the first systematic breakdown of disease rates for KCNA1 variants in different protein domains, uncovering potential location biases that influence genotype-phenotype correlations. Our examination of the new mutations strengthens the proposed link between the pore region and epilepsy and reveals new connections between epilepsy-related variants, genetic modifiers, and respiratory dysfunction. Additionally, the new variants include the first two gain-of-function mutations ever discovered for KCNA1, the first frameshift mutation, and the first mutations located in the cytoplasmic N-terminal domain, broadening the functional and molecular scope of KCNA1 channelopathy. Moreover, the recently identified variants highlight emerging links between KCNA1 and musculoskeletal abnormalities and nystagmus, conditions not typically associated with KCNA1. These findings improve our understanding of KCNA1 channelopathy and promise to enhance personalized diagnosis and treatment for individuals with KCNA1-linked disorders.

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The integrated stress response promotes neural stem cell survival under conditions of mitochondrial dysfunction in neurodegeneration

Iqbal,

Bilen,

Liu

et al. 2024

Aging Cell

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Impaired mitochondrial function is a hallmark of aging and a major contributor to neurodegenerative diseases. We have shown that disrupted mitochondrial dynamics typically found in aging alters the fate of neural stem cells (NSCs) leading to impairments in learning and memory. At present, little is known regarding the mechanisms by which neural stem and progenitor cells survive and adapt to mitochondrial dysfunction. Using Opa1‐inducible knockout as a model of aging and neurodegeneration, we identify a decline in neurogenesis due to impaired stem cell activation and progenitor proliferation, which can be rescued by the mitigation of oxidative stress through hypoxia. Through sc‐RNA‐seq, we identify the ATF4 pathway as a critical mechanism underlying cellular adaptation to metabolic stress. ATF4 knockdown in Opa1‐deficient NSCs accelerates cell death, while the increased expression of ATF4 enhances proliferation and survival. Using a Slc7a11 mutant, an ATF4 target, we show that ATF4‐mediated glutathione production plays a critical role in maintaining NSC survival and function under stress conditions. Together, we show that the activation of the integrated stress response (ISR) pathway enables NSCs to adapt to metabolic stress due to mitochondrial dysfunction and metabolic stress and may serve as a therapeutic target to enhance NSC survival and function in aging and neurodegeneration.

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Loss of functional System x-c uncouples aberrant postnatal neurogenesis from epileptogenesis in the hippocampus of Kcna1-KO mice

Cited by 7 publications

References 52 publications

Novel Genetic Variants Expand the Functional, Molecular, and Pathological Diversity of KCNA1 Channelopathy

Novel Genetic Variants Expand the Functional, Molecular, and Pathological Diversity of KCNA1 Channelopathy

Novel Genetic Variants Expand the Functional, Molecular and Pathological Diversity of KCNA1 Channelopathy

The integrated stress response promotes neural stem cell survival under conditions of mitochondrial dysfunction in neurodegeneration

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