PARL deficiency in mouse causes Complex III defects, coenzyme Q depletion, and Leigh-like syndrome

The mitochondrial intramembrane rhomboid protease PARL has been implicated in diverse functions in vitro, but its physiological role in vivo remains unclear. Here we show that ablation in mouse causes a necrotizing encephalomyelopathy similar to Leigh syndrome, a mitochondrial disease characterized by disrupted energy production. Mice with conditional PARL deficiency in the nervous system, but not in muscle, develop a similar phenotype as germline KOs, demonstrating the vital role of PARL in neurological homeostasis. Genetic modification of two major PARL substrates, PINK1 and PGAM5, do not modify this severe neurological phenotype. brain mitochondria are affected by progressive ultrastructural changes and by defects in Complex III (CIII) activity, coenzyme Q (CoQ) biosynthesis, and mitochondrial calcium metabolism. PARL is necessary for the stable expression of TTC19, which is required for CIII activity, and of COQ4, which is essential in CoQ biosynthesis. Thus, PARL plays a previously overlooked constitutive role in the maintenance of the respiratory chain in the nervous system, and its deficiency causes progressive mitochondrial dysfunction and structural abnormalities leading to neuronal necrosis and Leigh-like syndrome

Detection of insulin granule exocytosis by an electrophysiology method with high temporal resolution reveals enlarged insulin granule pool in BIG3-knockout mice

We recently identified BIG3 as a negative regulator of insulin granule biogenesis and reported increased insulin secretion in BIG3-knockout (BKO) mice. To pinpoint the site of action for BIG3, we investigated whether BIG3 regulates quantal insulin granule exocytosis. We established an assay to detect insulin granule exocytosis by recording ATP-elicited currents at high temporal resolution by patch clamp. Similarly to insulin, ATP release was increased in BKO β-cells. Although the frequency of insulin granule exocytosis was increased in BKO β-cells, quantal size or release kinetics remained unchanged. Electron microscopy studies showed that the number of insulin granules was increased by >60% in BKO β-cells. However, the number of morphologically docked granules was unaltered. The number of insulin granules having significant distances away from plasma membrane was greatly increased in BKO β-cells. Thus, BIG3 negatively regulates insulin granule exocytosis by restricting insulin granule biogenesis without the release kinetics of individual granules at the final exocytotic steps being affected. Depletion of BIG3 leads to an enlarged releasable pool of insulin granules, which accounts for increased release frequency and consequently increased insulin secretion

The non-coding RNA BC1 regulates experience-dependent structural plasticity and learning.

The brain cytoplasmic (BC1) RNA is a non-coding RNA (ncRNA) involved in neuronal translational control. Absence of BC1 is associated with altered glutamatergic transmission and maladaptive behavior. Here, we show that pyramidal neurons in the barrel cortex of BC1 knock out (KO) mice display larger excitatory postsynaptic currents and increased spontaneous activity in vivo. Furthermore, BC1 KO mice have enlarged spine heads and postsynaptic densities and increased synaptic levels of glutamate receptors and PSD-95. Of note, BC1 KO mice show aberrant structural plasticity in response to whisker deprivation, impaired texture novel object recognition and altered social behavior. Thus, our study highlights a role for BC1 RNA in experience-dependent plasticity and learning in the mammalian adult neocortex, and provides insight into the function of brain ncRNAs regulating synaptic transmission, plasticity and behavior, with potential relevance in the context of intellectual disabilities and psychiatric disorders.Brain cytoplasmic (BC1) RNA is a non-coding RNA that has been implicated in translational regulation, seizure, and anxiety. Here, the authors show that in the cortex, BC1 RNA is required for sensory deprivation-induced structural plasticity of dendritic spines, as well as for correct sensory learning and social behaviors

Digitalization of Russian Education: Changing Actors and Spaces of Governance

This chapter discusses the operation of digital education in relation to the changing governance of education in Russia. It examines how digitalization changes the character of traditional actors and enables new actors and actor assemblages to enter the scene of education governance and provision. It then looks at how datafication extends spaces of governance in both a topographical and a topological manner. Topographically, some practices of datafication follow established administrative structures enabling tighter vertical control over regions and education institutions by the federal authorities. But datafication also generates spaces that overcome topographical distance through relationality and connectedness. These manifest, first, in the possibilities of intimate governance reaching into individual subjectivities and, second, intensifying proximities to the global level of education governance bypassing the national authority.publishedVersionPeer reviewe