Norwegian moose CWD induces clinical disease and neuroinvasion in gene-targeted mice expressing cervid S138N prion protein.

Chronic wasting disease (CWD) is a prion disease affecting deer, elk and moose in North America and reindeer, moose and red deer in Northern Europe. Pathogenesis is driven by the accumulation of PrPSc, a pathological form of the host's cellular prion protein (PrPC), in the brain. CWD is contagious among North American cervids and Norwegian reindeer, with prions commonly found in lymphatic tissue.

Anti-prion drugs do not improve survival in novel knock-in models of inherited prion disease.

Prion diseases uniquely manifest in three distinct forms: inherited, sporadic, and infectious. Wild-type prions are responsible for the sporadic and infectious versions, while mutant prions cause inherited variants like fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (fCJD). Although some drugs can prolong prion incubation times up to four-fold in rodent models of infectious prion diseases, no effective treatments for FFI and fCJD have been found.

DNA G-Quadruplex Is a Transcriptional Control Device That Regulates Memory.

The conformational state of DNA fine-tunes the transcriptional rate and abundance of RNA. Here, we report that G-quadruplex DNA (G4-DNA) accumulates in neurons, in an experience-dependent manner, and that this is required for the transient silencing and activation of genes that are critically involved in learning and memory in male C57/BL6 mice. In addition, site-specific resolution of G4-DNA by dCas9-mediated deposition of the helicase DHX36 impairs fear extinction memory.

Selective Vulnerability to Neurodegenerative Disease: Insights from Cell Type-Specific Translatome Studies.

Neurodegenerative diseases (NDs) manifest a wide variety of clinical symptoms depending on the affected brain regions. Gaining insights into why certain regions are resistant while others are susceptible is vital for advancing therapeutic strategies. While gene expression changes offer clues about disease responses across brain regions, the mixture of cell types therein obscures experimental results.

Anti-prion drugs do not improve survival in knock-in models of inherited prion disease.

Prion diseases uniquely manifest in three distinct forms: inherited, sporadic, and infectious. Wild-type prions are responsible for the sporadic and infectious versions, while mutant prions cause inherited variants like fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (fCJD). Although some drugs can prolong prion incubation times up to four-fold in rodent models of infectious prion diseases, no effective treatments for FFI and fCJD have been found.

Effect of Transcutaneous Spinal Direct Current Stimulation in Patients with Painful Polyneuropathy and Influence of Possible Predictors of Efficacy including BDNF Polymorphism: A Randomized, Sham-Controlled Crossover Study.

: The neuromodulating effects of transcutaneous-spinal Direct Current Stimulation (tsDCS) have been reported to block pain signaling. For patients with chronic pain, tsDCS could be a potential treatment option. To approach this, we studied the effect of anodal tsDCS on patients with neuropathic pain approaching an optimal paradigm including the investigation of different outcome predictors.

Cerebellar granule neurons induce Cyclin D1 before the onset of motor symptoms in Huntington's disease mice.

Although Huntington's disease (HD) is classically defined by the selective vulnerability of striatal projection neurons, there is increasing evidence that cerebellar degeneration modulates clinical symptoms. However, little is known about cell type-specific responses of cerebellar neurons in HD. To dissect early disease mechanisms in the cerebellum and cerebrum, we analyzed translatomes of neuronal cell types from both regions in a new HD mouse model.

Therapeutic Trial of anle138b in Mouse Models of Genetic Prion Disease.

Phenotypic screening has yielded small-molecule inhibitors of prion replication that are effective against certain prion strains but not others. Here, we sought to test the small molecule anle138b in multiple mouse models of prion disease. In mice inoculated with the RML strain of prions, anle138b doubled survival and durably suppressed astrogliosis measured by live-animal bioluminescence imaging.

Correction: Tagger-A Swiss army knife for multiomics to dissect cell type-specific mechanisms of gene expression in mice.

[This corrects the article DOI: 10.1371/journal.pbio.

Translatome profiling in fatal familial insomnia implicates TOR signaling in somatostatin neurons.

Selective neuronal vulnerability is common in neurodegenerative diseases but poorly understood. In genetic prion diseases, including fatal familial insomnia (FFI) and Creutzfeldt-Jakob disease (CJD), different mutations in the gene manifest as clinically and neuropathologically distinct diseases. Here we report with electroencephalography studies that theta waves are mildly increased in 21 mo old knock-in mice modeling FFI and CJD and that sleep is mildy affected in FFI mice.

Clearance of variant Creutzfeldt-Jakob disease prions in vivo by the Hsp70 disaggregase system.

The metazoan Hsp70 disaggregase protects neurons from proteotoxicity that arises from the accumulation of misfolded protein aggregates. Hsp70 and its co-chaperones disassemble and extract polypeptides from protein aggregates for refolding or degradation. The effectiveness of the chaperone system decreases with age and leads to accumulation rather than removal of neurotoxic protein aggregates.

CalDAG-GEFI mediates striatal cholinergic modulation of dendritic excitability, synaptic plasticity and psychomotor behaviors.

CalDAG-GEFI (CDGI) is a protein highly enriched in the striatum, particularly in the principal spiny projection neurons (SPNs). CDGI is strongly down-regulated in two hyperkinetic conditions related to striatal dysfunction: Huntington's disease and levodopa-induced dyskinesia in Parkinson's disease. We demonstrate that genetic deletion of CDGI in mice disrupts dendritic, but not somatic, M1 muscarinic receptors (M1Rs) signaling in indirect pathway SPNs.

Slc1a3-2A-CreERT2 mice reveal unique features of Bergmann glia and augment a growing collection of Cre drivers and effectors in the 129S4 genetic background.

Genetic variation is a primary determinant of phenotypic diversity. In laboratory mice, genetic variation can be a serious experimental confounder, and thus minimized through inbreeding. However, generalizations of results obtained with inbred strains must be made with caution, especially when working with complex phenotypes and disease models.

Memory trace interference impairs recall in a mouse model of Alzheimer's disease.

In Alzheimer's disease (AD), hippocampus-dependent memories underlie an extensive decline. The neuronal ensemble encoding a memory, termed engram, is partially recapitulated during memory recall. Artificial activation of an engram can restore memory in a mouse model of early AD, but its fate and the factors that render the engram nonfunctional are yet to be revealed.

Tagger-A Swiss army knife for multiomics to dissect cell type-specific mechanisms of gene expression in mice.

A deep understanding of how regulation of the multiple levels of gene expression in mammalian tissues give rise to complex phenotypes has been impeded by cellular diversity. A handful of techniques were developed to tag-select nucleic acids of interest in specific cell types, thereby enabling their capture. We expanded this strategy by developing the Tagger knock-in mouse line bearing a quad-cistronic transgene combining enrichment tools for nuclei, nascent RNA, translating mRNA, and mature microRNA (miRNA).

Stroke target identification guided by astrocyte transcriptome analysis.

Astrocytes support normal brain function, but may also contribute to neurodegeneration when they become reactive under pathological conditions such as stroke. However, the molecular underpinnings of this context-dependent interplay between beneficial and detrimental properties in reactive astrogliosis have remained incompletely understood. Therefore, using the RiboTag technique, we immunopurified translating mRNAs specifically from astrocytes 72 hr after transient middle cerebral artery occlusion in mice (tMCAO), thereby generating a stroke-specific astroglial translatome database.

Epigenetic alterations in longevity regulators, reduced life span, and exacerbated aging-related pathology in old father offspring mice.

Advanced age is not only a major risk factor for a range of disorders within an aging individual but may also enhance susceptibility for disease in the next generation. In humans, advanced paternal age has been associated with increased risk for a number of diseases. Experiments in rodent models have provided initial evidence that paternal age can influence behavioral traits in offspring animals, but the overall scope and extent of paternal age effects on health and disease across the life span remain underexplored.

Genetic human prion disease modelled in PrP transgenic .

Inherited human prion diseases, such as fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (fCJD), are associated with autosomal dominant mutations in the human prion protein gene and accumulation of PrP, an abnormal isomer of the normal host protein PrP, in the brain of affected individuals. PrP is the principal component of the transmissible neurotoxic prion agent. It is important to identify molecular pathways and cellular processes that regulate prion formation and prion-induced neurotoxicity.

The natural Disc1-deletion present in several inbred mouse strains does not affect sleep.

The gene Disrupted in Schizophrenia-1 (DISC1) is linked to a range of psychiatric disorders. Two recent transgenic studies suggest DISC1 is also involved in homeostatic sleep regulation. Several strains of inbred mice commonly used for genome manipulation experiments, including several Swiss and likely all 129 substrains, carry a natural deletion mutation of Disc1.

Manipulating the Prion Protein Gene Sequence and Expression Levels with CRISPR/Cas9.

The mammalian prion protein (PrP, encoded by Prnp) is most infamous for its central role in prion diseases, invariably fatal neurodegenerative diseases affecting humans, food animals, and animals in the wild. However, PrP is also hypothesized to be an important receptor for toxic protein conformers in Alzheimer's disease, and is associated with other clinically relevant processes such as cancer and stroke. Thus, key insights into important clinical areas, as well as into understanding PrP functions in normal physiology, can be obtained from studying transgenic mouse models and cell culture systems.