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| Open AccessA Protein Misfolding Shaking Amplification-based method for the spontaneous generation of hundreds of bona fide prions
To study neurodegenerative prion diseases, a method (PMSA) for generating prions spontaneously is presented. Applied to 380+ different prion proteins, their tendency to become pathogenic was ranked, illuminating their formation process.
- Hasier Eraña
- , Cristina Sampedro-Torres-Quevedo
- & Joaquín Castilla
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Article
| Open AccessEpilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability
CDKL5 deficiency disorder is one of the most common genetic forms of epilepsy. Here the authors show that a model of CDKL5 deficiency disorder involves a channelopathy of CACNA1E gain-of-function, molecularly linking two distinct single-gene developmental and epileptic encephalopathies.
- Marisol Sampedro-Castañeda
- , Lucas L. Baltussen
- & Sila K. Ultanir
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Article
| Open AccessEffects of oxidative stress on hepatic encephalopathy pathogenesis in mice
Oxidative stress plays a crucial role in the pathogenesis of hepatic encephalopathy (HE). Here, authors show that the chemogenetic inhibition of GAD2 population in the SNr region, or the targeted overexpression of mitochondrial UCP2 in such population, or systemic application of a mitochondrial-targeting antioxidant drug Mito-Q could effectively ameliorate HE.
- Yunhu Bai
- , Kenan Li
- & Yanling Yang
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Article
| Open AccessCryo-EM structure of anchorless RML prion reveals variations in shared motifs between distinct strains
The authors report the near-atomic structure of the ex vivo aRML prion fibril. The comparison between this structure and the previously solved 263K prion fibril shows that both common and divergent features characterize these prion strains and their respective conformational replication templates.
- Forrest Hoyt
- , Heidi G. Standke
- & Allison Kraus
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Article
| Open AccessGain-of-function and loss-of-function GABRB3 variants lead to distinct clinical phenotypes in patients with developmental and epileptic encephalopathies
Genetic variants of γ-aminobutyric acid (GABAA) receptors are associated with early onset epilepsies. Here, the authors show that functional loss or gain-of-function defines clinical outcomes, with gain-of-function variants unexpectedly more severe.
- Nathan L. Absalom
- , Vivian W. Y. Liao
- & Philip K. Ahring
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Article
| Open AccessNeuropathology and virus in brain of SARS-CoV-2 infected non-human primates
COVID-19 can result in neurological manifestations and animal models could provide insights into the mechanisms. Here, the authors describe neuroinflammation, microhemorrhages and brain hypoxia in SARS-CoV-2 infected non-human primates, including in animals that don’t develop severe respiratory disease.
- Ibolya Rutkai
- , Meredith G. Mayer
- & Tracy Fischer
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Article
| Open AccessScn1a gene reactivation after symptom onset rescues pathological phenotypes in a mouse model of Dravet syndrome
Dravet syndrome is a devastating epileptic encephalopathy caused by Scn1a gene haploinsufficiency. Exploiting a novel knock-in mouse model, here the authors show that restoring Scn1a expression after symptom onset is sufficient to rescue main phenotypic manifestations of the syndrome.
- Nicholas Valassina
- , Simone Brusco
- & Gaia Colasante
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Article
| Open AccessDALRD3 encodes a protein mutated in epileptic encephalopathy that targets arginine tRNAs for 3-methylcytosine modification
METTL2 methyltransferase is responsible for 3-methylcytosine modification of arginine tRNAs in mammals. Here the authors show that DALR anticodon binding domain containing 3 (DALRD3) forms a complex with METTL2 to recognize specific arginine tRNAs and find DALRD3 mutations in patients with developmental delay and early-onset epileptic encephalopathy.
- Jenna M. Lentini
- , Hessa S. Alsaif
- & Dragony Fu
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Article
| Open AccessLoss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy
UDP-glucuronic acid is a component of the extracellular matrix. Here, the authors report biallelic variants in the gene encoding UDP-Glucose 6-Dehydrogenase (UGDH) in individuals affected by developmental epileptic encephalopathies that impair UGDH stability, oligomerization, or enzymatic activity in vitro.
- Holger Hengel
- , Célia Bosso-Lefèvre
- & Bruno Reversade
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Article
| Open AccessBiallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy
Valyl-tRNA synthetase (VARS) charges valyl-tRNA with the amino acid valine, required for translation. Here, the authors describe a progressive epileptic encephalopathy in individuals from five families carrying biallelic mutations in the VARS gene that leave the enzyme activity partially intact.
- Jennifer Friedman
- , Desiree E. Smith
- & Joseph G. Gleeson
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Article
| Open AccessBiallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish
tRNAs are linked with their cognate amino acid by aminoacyl tRNA synthetases (ARS). Here, the authors report a developmental encephalopathy associated with biallelic VARS variants (valyl-tRNA synthetase) that lead to loss of function, as determined by several in vitro assays and a vars knockout zebrafish model.
- Aleksandra Siekierska
- , Hannah Stamberger
- & Peter De Jonghe
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Article
| Open AccessThe HIF-1/glial TIM-3 axis controls inflammation-associated brain damage under hypoxia
The targeting of inflammation has emerged as a promising therapeutic strategy for cerebral ischaemia. Here the authors show that TIM-3, a member of the T-cell immunoglobulin and mucin domain protein family, is upregulated in glial cells and plays a role in inflammation-associated brain injury under hypoxic conditions.
- Han Seok Koh
- , Chi Young Chang
- & Eun Jung Park