No abstract

Objective SCN8A encephalopathy is a developmental and epileptic encephalopathy (DEE) caused by de novo gain‐of‐function mutations of sodium channel Nav1.6 that result in neuronal hyperactivity. Affected individuals exhibit early onset drug‐resistant seizures, developmental delay, and cognitive impairment. This study was carried out to determine whether reducing the abundance of the Scn8a transcript with an antisense oligonucleotide (ASO) would delay seizure onset and prolong survival in a mouse model of SCN8A encephalopathy. Methods ASO treatment was tested in a conditional mouse model with Cre‐dependent expression of the pathogenic patient SCN8A mutation p.Arg1872Trp (R1872W). This model exhibits early onset of seizures, rapid progression, and 100% penetrance. An Scn1a +/− haploinsufficient mouse model of Dravet syndrome was also treated. ASO was administered by intracerebroventricular injection at postnatal day 2, followed in some cases by stereotactic injection at postnatal day 30. Results We observed a dose‐dependent increase in length of survival from 15 to 65 days in the Scn8a‐R1872W/+ mice treated with ASO. Electroencephalographic recordings were normal prior to seizure onset. Weight gain and activity in an open field were unaffected, but treated mice were less active in a wheel running assay. A single treatment with Scn8a ASO extended survival of Dravet syndrome mice from 3 weeks to >5 months. Interpretation Reduction of Scn8a transcript by 25 to 50% delayed seizure onset and lethality in mouse models of SCN8A encephalopathy and Dravet syndrome. Reduction of SCN8A transcript is a promising approach to treatment of intractable childhood epilepsies. Ann Neurol 2020;87:339–346

Cardiolipin (CL) is a mitochondrial phospholipid with a very specific and functionally important fatty acid composition, generated by tafazzin. However, in vitro tafazzin catalyzes a promiscuous acyl exchange that acquires specificity only in response to perturbations of the physical state of lipids. To identify the process that imposes acyl specificity onto CL remodeling in vivo, we analyzed a series of deletions and knockdowns in Saccharomyces cerevisiae and Drosophila melanogaster, including carriers, membrane homeostasis proteins, fission-fusion proteins, cristae-shape controlling and MICOS proteins, and the complexes I–V. Among those, only the complexes of oxidative phosphorylation (OXPHOS) affected the CL composition. Rather than any specific complex, it was the global impairment of the OXPHOS system that altered CL and at the same time shortened its half-life. The knockdown of OXPHOS expression had the same effect on CL as the knockdown of tafazzin in Drosophila flight muscles, including a change in CL composition and the accumulation of monolyso-CL. Thus, the assembly of OXPHOS complexes induces CL remodeling, which, in turn, leads to CL stabilization. We hypothesize that protein crowding in the OXPHOS system imposes packing stress on the lipid bilayer, which is relieved by CL remodeling to form tightly packed lipid–protein complexes.

No abstract

Valproic acid and lithium are widely used to treat bipolar disorder, a severe illness characterized by cycles of mania and depression. However, their efficacy is limited, and treatment is often accompanied by serious side effects. The therapeutic mechanisms of these drugs are not understood, hampering the development of more effective treatments. Among the plethora of biochemical effects of the drugs, those that are common to both may be more related to therapeutic efficacy. Two common outcomes include inositol depletion and GSK3 inhibition, which have been proposed to explain the efficacy of both valproic acid and lithium. Here, we discuss the inositol depletion and GSK3 inhibition hypotheses, and introduce a unified model suggesting that inositol depletion and GSK3 inhibition are inter-related.