Mouse Disease ((BETTER))
Huntington's disease is a neurodegenerative disorder caused by a polyglutamine repeat in the Huntingtin gene (HTT). Although suppressing the expression of mutant HTT (mHTT) has been explored as a therapeutic strategy to treat Huntington's disease, considerable efforts have gone into developing allele-specific suppression of mHTT expression, given that loss of Htt in mice can lead to embryonic lethality. It remains unknown whether depletion of HTT in the adult brain, regardless of its allele, could be a safe therapy. Here, we report that permanent suppression of endogenous mHTT expression in the striatum of mHTT-expressing mice (HD140Q-knockin mice) using CRISPR/Cas9-mediated inactivation effectively depleted HTT aggregates and attenuated early neuropathology. The reduction of mHTT expression in striatal neuronal cells in adult HD140Q-knockin mice did not affect viability, but alleviated motor deficits. Our studies suggest that non-allele-specific CRISPR/Cas9-mediated gene editing could be used to efficiently and permanently eliminate polyglutamine expansion-mediated neuronal toxicity in the adult brain.
Foot and mouth disease (FMD) is a severe, highly contagious viral disease of livestock that has a significant economic impact. The disease affects cattle, swine, sheep, goats and other cloven-hoofed ruminants. It is a transboundary animal disease (TAD) that deeply affect the production of livestock and disrupting regional and international trade in animals and animal products. The disease is estimated to circulate in 77% of the global livestock population, in Africa, the Middle East and Asia, as well as in a limited area of South America. Countries that are currently free of FMD without vaccination remain under constant threat of an incursion. Seventy-five percent of the costs attributed to FMD prevention and control are incurred by low income and lower-middle income countries. Africa and Eurasia are the regions which incur the largest costs, accounting for 50% and 33% of the total costs respectively. FMD is caused by an Aphthovirus of the family Picornaviridae, seven strains (A, O, C, SAT1, SAT2, SAT3, and Asia1) are endemic in different countries worldwide. Each strain requires a specific vaccine to provide immunity to a vaccinated animal. Its prevention is based on the presence of early detection and warning systems and the implementation of effective surveillance among other measures. FMD is the first disease for which the OIE established an official list of disease-free countries which can be officially recognised as free of the disease either in their entirety or in defined zones and compartments.
Foot and mouth disease (FMD) is a severe, highly contagious viral disease of livestock that has a significant economic impact. The disease affects cattle, swine, sheep, goats and other cloven-hoofed ruminants.
Intensively reared animals are more susceptible to the disease than traditional breeds. The disease is rarely fatal in adult animals, but there is often high mortality in young animals due to myocarditis or, when the dam is infected by the disease, lack of milk.
FMD is characterised by fever and blister-like sores on the tongue and lips, in the mouth, on the teats and between the hooves. The disease causes severe production losses, and while the majority of affected animals recover, the disease often leaves them weakened and debilitated.
All seven of the serotypes have also been found in wildlife, although the latter does not play a significant role in the maintenance of the disease. To date, the only confirmed reservoir in wildlife is African buffalo Syncerus caffer).
It was the first disease for which the World Organisation for Animal Health (WOAH, founded as OIE) established official status recognition. Members can also apply for official endorsement of their national control programmes.
The disease may be suspected based on clinical signs. However, FMD cannot be differentiated clinically from other vesicular diseases, such as swine vesicular disease, vesicular stomatitis and vesicular exanthema.
The initial measures described in the Global Food and Mouth disease control strategy are the presence of early detection and warning systems and the implementation of effective surveillance in accordance with the guidelines detailed in the Terrestrial Code. They help monitor the occurrence and prevalence of the disease and allow characterisation of FMD viruses.
Australia, New Zealand, Indonesia, Central and North America, and continental Western Europe are currently free of FMD. However, FMD is a transboundary animal disease that can occur sporadically in any typically free area.
In accordance with the WOAH procedure for official recognition of disease status, this page provides access to the List of WOAH Members officially recognised free from foot and mouth disease (FMD) by the WOAH through the adoption of a resolution by the World Assembly of Delegates (Assembly) of the WOAH at the General Session in May every year.
Subsequent to a disease outbreak or when the Scientific Commission determines that the conditions are not met anymore to demonstrate compliance with the relevant requirements of the Terrestrial Code, a disease status may be suspended. The Scientific Commission may decide to reinstate the suspended status when a Member has submitted an application which fulfils all the requirements requested for the recovery of official disease status laid out in the relevant Chapters of the Terrestrial Code. The suspensions and recoveries of disease status are announced by the Director General of the WOAH in consultation with the Scientific Commission and the list of these is kept up to date until adoption of a new resolution by the Assembly the following May.
The CRISPR-Cas9 system has been employed to generate mutant alleles in a range of different organisms. However, so far there have not been reports of use of this system for efficient correction of a genetic disease. Here we show that mice with a dominant mutation in Crygc gene that causes cataracts could be rescued by coinjection into zygotes of Cas9 mRNA and a single-guide RNA (sgRNA) targeting the mutant allele. Correction occurred via homology-directed repair (HDR) based on an exogenously supplied oligonucleotide or the endogenous WT allele, with only rare evidence of off-target modifications. The resulting mice were fertile and able to transmit the corrected allele to their progeny. Thus, our study provides proof of principle for use of the CRISPR-Cas9 system to correct genetic disease.
Alzheimer's disease (AD) is characterized by amyloid-beta (Abeta) and tau deposition in brain. It has emerged that Abeta toxicity is tau dependent, although mechanistically this link remains unclear. Here, we show that tau, known as axonal protein, has a dendritic function in postsynaptic targeting of the Src kinase Fyn, a substrate of which is the NMDA receptor (NR). Missorting of tau in transgenic mice expressing truncated tau (Deltatau) and absence of tau in tau(-/-) mice both disrupt postsynaptic targeting of Fyn. This uncouples NR-mediated excitotoxicity and hence mitigates Abeta toxicity. Deltatau expression and tau deficiency prevent memory deficits and improve survival in Abeta-forming APP23 mice, a model of AD. These deficits are also fully rescued with a peptide that uncouples the Fyn-mediated interaction of NR and PSD-95 in vivo. Our findings suggest that this dendritic role of tau confers Abeta toxicity at the postsynapse with direct implications for pathogenesis and treatment of AD.
Impressive advances in defining the properties of receptors for the Fc portion of immunoglobulins (FcR) have been made over the past several years. Ligand specificities were systematically analyzed for both human and mouse FcRs that revealed novel receptors for specific IgG subclasses. Expression patterns were redefined using novel specific anti-FcR mAbs that revealed major differences between human and mouse systems. The in vivo roles of IgG receptors have been addressed using specific FcR knockout mice or in mice expressing a single FcR, and have demonstrated a predominant contribution of mouse activating IgG receptors FcγRIII and FcγRIV to models of autoimmunity (eg, arthritis) and allergy (eg, anaphylaxis). Novel blocking mAbs specific for these activating IgG receptors have enabled, for the first time, the investigation of their roles in vivo in wild-type mice. In parallel, the in vivo properties of human FcRs have been reported using transgenic mice and models of inflammatory and allergic reactions, in particular those of human activating IgG receptor FcγRIIA (CD32A). Importantly, these studies led to the identification of specific cell populations responsible for the induction of various inflammatory diseases and have revealed, in particular, the unexpected contribution of neutrophils and monocytes to the induction of anaphylactic shock.
Mouse IgG receptors. Schematic representation of mouse IgG receptors at the cell membrane (gray bar) and their association or not to the FcRγ-chain dimer (black). Green boxes represent ITAMs; and the white box, the ITIM. Binding of a mouse IgG subclass is indicated in bold (high affinity), plain (low affinity), or between parentheses (very low affinity). - indicates no binding.
Novel specific mAbs generated against mouse FcγRs have facilitated the examination of the expression pattern of FcγRIII and of the newly cloned FcγRIV. Reports in wild-type (WT) mice have described FcγRI to be restricted to monocyte-derived DCs,33,34 FcγRIV to be restricted to Ly6Clo monocytes,35 macrophages, and neutrophils,26 whereas FcγRIIB and FcγRIII were shown to be expressed on all myeloid populations12 ; FcγRIIB is also expressed on B cells and FcγRIII also on NK and NKT cells.36 FcRn is expressed on antigen-presenting cells on neutrophils,4 on splenic monocytes and B cells,37 on the vascular endothelium, and, during the neonatal period, on epithelial cells of the intestine17 (Table 3). Among the newly described FcR-specific mAbs, blocking mAbs were characterized for FcγRIII (clone 275003)38 and FcγRIV (clone 9E9).24 FcγRIIB-specific blocking mAbs (clone K75.325 anti-Ly17.1 haplotype or clone K9.361 anti-Ly17.2 haplotype) were described in the 1980s.29 However, a FcγRI-specific blocking mAb has still not been reported. 041b061a72