Stress responses are cellular processes essential for maintenance of cellular integrity and defense against environmental and intracellular insults. Neurodegenerative conditions are linked with inadequate stress responses. Several stress-responsive genes encoding neuroprotective proteins have been identified, and among them, the heat shock proteins comprise an important group of molecular chaperones that have neuroprotective functions. However, evidence for other critical stressresponsive genes is lacking. Recent studies on the NAD synthesis enzyme nicotinamide mononucleotide adenylyltransferase (NMNAT) have uncovered a novel neuronal maintenance and protective function against activity-, injury-, or misfolded protein-induced degeneration in Drosophila and in mammalian neurons. Here, we show that NMNAT is also a novel stress response protein required for thermotolerance and mitigation of oxidative stress-induced shortened lifespan. NMNAT is transcriptionally regulated during various stress conditions including heat shock and hypoxia through heat shock factor (HSF) and hypoxia-inducible factor 1␣ in vivo. HSF binds to nmnat promoter and induces NMNAT expression under heat shock. In contrast, under hypoxia, HIF1␣ up-regulates NMNAT indirectly through the induction of HSF. Our studies provide an in vivo mechanism for transcriptional regulation of NMNAT under stress and establish an essential role for this neuroprotective factor in cellular stress response.When faced with abnormal conditions, such as heat, oxidative stress, hypoxia, or accumulation of aberrant proteins, cells implement a stress response program to protect themselves and ensure survival. Stress conditions can cause protein unfolding, misfolding, or aggregation, and the consequent inadequate response to stress can lead to developmental defects, shortened lifespan, and neurodegenerative conditions (for review, see Ref.2). The increased synthesis of molecular chaperone heat shock proteins (HSPs) 2 is central to the stress response because they function to prevent protein misfolding and aggregation to maintain protein homeostasis (1, 2). It is thought that elevated expression of HSPs is sufficient to protect cells from a wide range of cytotoxic conditions (1, 3, 4). However, it is unclear whether the stress response network includes essential genes other than HSPs. Although a few metabolic enzymes have been found to be up-regulated upon stress (5, 6), it is unclear whether metabolic enzymes are an integral part of the stress response network.Heat shock factors (HSFs) are the master stress transcription factors of heat shock response, with one HSF in invertebrates and multiple HSFs in plants and vertebrates (7-9). Through their roles in mediating transcriptional activation of HSP genes, HSFs function in maintaining protein homeostasis and integrating cellular response to stress and development (10). Upregulation of HSPs by HSF1 is triggered by a variety of acute and chronic stress conditions and disease states (11). When faced with other stress conditio...

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Background: Acetylcholinesterase RNA and protein are concentrated at the neuromuscular synapse but how its translation is regulated is not known. Results: The translational repressor Pumilio-2 is localized at the neuromuscular synapse where it binds acetylcholinesterase mRNA. Conclusions: Pumilio-2 regulates acetylcholinesterase expression at the neuromuscular synapse. Significance: Translational control of synaptic proteins can regulate synaptic transmission; changing acetylcholinesterase levels could influence sensitivity of cholinergic synapses.

In jawed vertebrates, oligodendrocytes (OLs) are the myelin-producing glial cells responsible for ensheathment of axons within the central nervous system and are also crucial for remyelination following injury or disease. Olig2 is a crucial factor in the specification and differentiation of oligodendrocyte precursor cells (OPCs) that give rise to mature, myelin-producing OLs in the developing and postnatal CNS; however, its role in adulthood is less well understood. To investigate the role Olig2 plays in regulating gene expression in the adult OL lineage in a physiologically-relevant context, we performed chromatin immunoprecipitation followed by next generation sequencing analysis (ChIP-Seq) using whole spinal cord tissue harvested from adult mice.We found that many of the Olig2-bound sites were associated with genes with biological processes corresponding to OL differentiation (Nkx2.2, Nkx6.2, and Sip1), myelination and ensheathment (Mbp, Cldn11, and Mobp), as well as cell cycle and cytoskeletal regulation. This suggests Olig2 continues to play a critical role in processes related to OL differentiation and myelination well into adulthood.

Spinal Cord Injury (SCI) results in severe sub-lesional muscle atrophy and fiber type transformation from slow oxidative to fast glycolytic, both contributing to functional deficits and maladaptive metabolic profiles. Therapeutic countermeasures have had limited success and muscle-related pathology remains a clinical priority. mTOR signaling is known to play a critical role in skeletal muscle growth and metabolism, and signal integration of anabolic and catabolic pathways. Recent studies show that the natural compound ursolic acid (UA) enhances mTOR signaling intermediates, independently inhibiting atrophy and inducing hypertrophy. Here, we examine the effects of UA treatment on sub-lesional muscle mTOR signaling, catabolic genes, and functional deficits following severe SCI in mice. We observe that UA treatment significantly attenuates SCI induced decreases in activated forms of mTOR, and signaling intermediates PI3K, AKT, and S6K, and the upregulation of catabolic genes including FOXO1, MAFbx, MURF-1, and PSMD11. In addition, UA treatment improves SCI induced deficits in body and sub-lesional muscle mass, as well as functional outcomes related to muscle function, motor coordination, and strength. These findings provide evidence that UA treatment may be a potential therapeutic strategy to improve muscle-specific pathological consequences of SCI.