Current Methods In ALS Research.

ARTICLES DISCUSSED: Asakawa, K., Handa, H., Kawakami, K. Optogenetic phase transition of TDP-43 in spinal motor neurons of zebrafish larvae. Journal of Visualized Experiments. (180), e62932 (2022). Coyne, A. N., Rothstein, J. D. Nuclei isolation and super-resolution structured illumination microscopy for examining nucleoporin alterations in human neurodegeneration. (175), e62789 (2021). Currey, H. N., Liachko, N. F. Evaluation of motor impairment in C. elegans models of amyotrophic lateral sclerosis. (175), e62699 (2021). Hayes, L. R., Duan, L., Vidensky, S., Kalab, P. Nuclear transport assays in permeabilized mouse cortical neurons. (173), e62710 (2021). Krishnamurthy, K., Trotti, D., Pasinelli, P., Jensen, B. Real-time fluorescent measurements of synaptic functions in models of amyotrophic lateral sclerosis. (173), e62813 (2021). Loganathan, S., Ball H. E., Manzo, E., Zarnescu, D. C. Measuring glucose uptake in Drosophila models of TDP-43 proteinopathy. (174), e62936 (2021). Stilwell, G., Agudelo, A. Dissection and immunohistochemistry of the Drosophila adult leg to detect changes at the neuromuscular junction for an identified motor neuron. (180), e62844 (2022) Taga, A. et al. Establishment of an electrophysiological platform for modeling ALS with regionally-specific human pluripotent stem cell-derived astrocytes and neurons. (174), e62726 (2021). Stoklund Dittlau, K. et al., Generation of human motor units with functional neuromuscular junctions in microfluidic devices. (175), e62959 (2021).

HDAC3 Inhibition Stimulates Myelination in a CMT1A Mouse Model.

Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy, with currently no effective treatment or cure. CMT1A is caused by a duplication of the PMP22 gene, which leads to Schwann cell differentiation defects and dysmyelination of the peripheral nerves. The epigenetic regulator histone deacetylase 3 (HDAC3) has been shown to negatively regulate myelination as well as its associated signaling pathways, PI3K-AKT and MAPK-ERK. We showed that these signaling pathways are indeed downregulated in the C3-PMP22 mouse model, similar to what has been shown in the CMT1A rat model. We confirmed that early postnatal defects are present in the peripheral nerves of the C3-PMP22 mouse model, which led to a progressive reduction in axon caliber size and myelination. The aim of this study was to investigate whether pharmacological HDAC3 inhibition could be a valuable therapeutic approach for this CMT1A mouse model. We demonstrated that early treatment of CMT1A mice with the selective HDAC3 inhibitor RGFP966 increased myelination and myelin g-ratios, which was associated with improved electrophysiological recordings. However, a high dose of RGFP966 caused a decline in rotarod performance and a decline in overall grip strength. Additionally, macrophage presence in peripheral nerves was increased in RGFP966 treated CMT1A mice. We conclude that HDAC3 does not only play a role in regulating myelination but is also important in the neuroimmune modulation. Overall, our results indicate that correct dosing of HDAC3 inhibitors is of crucial importance if translated to a clinical setting for demyelinating forms of CMT or other neurological disorders.

Lighting Up the Plasma Membrane: Development and Applications of Fluorescent Ligands for Transmembrane Proteins.

Despite the fact that transmembrane proteins represent the main therapeutic targets for decades, complete and in-depth knowledge about their biochemical and pharmacological profiling is not fully available. In this regard, target-tailored small-molecule fluorescent ligands are a viable approach to fill in the missing pieces of the puzzle. Such tools, coupled with the ability of high-precision optical techniques to image with an unprecedented resolution at a single-molecule level, helped unraveling many of the conundrums related to plasma proteins' life-cycle and druggability. Herein, we review the recent progress made during the last two decades in fluorescent ligand design and potential applications in fluorescence microscopy of voltage-gated ion channels, ligand-gated ion channels and G-coupled protein receptors.

Opportunities for histone deacetylase inhibition in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. ALS patients suffer from a progressive loss of motor neurons, leading to respiratory failure within 3 to 5 years after diagnosis. Available therapies only slow down the disease progression moderately or extend the lifespan by a few months. Epigenetic hallmarks have been linked to the disease, creating an avenue for potential therapeutic approaches. Interference with one class of epigenetic enzymes, histone deacetylases, has been shown to affect neurodegeneration in many preclinical models. Consequently, it is crucial to improve our understanding about histone deacetylases and their inhibitors in (pre)clinical models of ALS. We conclude that selective inhibitors with high tolerability and safety and sufficient blood-brain barrier permeability will be needed to interfere with both epigenetic and non-epigenetic targets of these enzymes. LINKED ARTICLES: This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.6/issuetoc.

6-[6-(Pyridin-2-yl)-1,2,4,5-tetra-zin-3-yl]pyridin-3-amine monohydrate.

The packing of the title compound, C12H9N7·H2O, is dominated by hydrogen bonding and π-stacking. Layers parallel to [010] are established by hydrogen bonds involving all amine donor functions and one of the water donor functions, while the remaining water donor function enables the stacking of the layers along [10-1], which is accompanied by π-stacking. In the molecule, the plane of the central tetra-zine ring forms angles of 5.33 (7) and 19.84 (8)° with the adjacent 3-amine-pyridine and pyridine rings, respectively.